sports medicine Volume 38 Issue 11 November 2008

Sports Med 2008; 38 (11): 881-891 0112-1642/08/0011-0881/$48.00/0

LEADING ARTICLE

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Strategies for Improving Performance in Long Duration Events Olympic Distance Triathlon Christophe Hausswirth1 and Jeanick Brisswalter2 1 Institut National du Sport et de L’Education Physique (INSEP), Research Mission, Laboratory of Biomechanics and Physiology, Paris, France 2 Sport Ergonomics and Performance Laboratory, University of Toulon-Var, La Garde, France

Abstract

This review focuses on strategic aspects that may affect performance in a long-duration Olympic event, the Olympic distance triathlon. Given the variety of races during the Olympic Games triathlon, strategic aspects include improving technological features as well as energetics factors affecting overall triathlon performance. During the last decade, many studies have attempted to identify factors reducing the metabolic load associated (or not) with the development of fatigue process by analysing the relationship between metabolic and biomechanical factors with exercise duration. To date, a consensus exists about the benefit of adopting a drafting position during the swimming or the cycling part of the triathlon. Other potential strategic factors, such as the production of power output or the selection of cadence during the cycling or the running leg, are likely to affect the overall triathlon performance. Within this approach, pacing strategies are observed by elite athletes who swim or cycle in a sheltered position, inducing several changes of pace, intensity or stochastic shifts in the amplitude of the physiological responses. The analysis of these parameters appears to arouse some experimental and practical interest from researchers and coachers, especially for long-distance Olympic events.

In human locomotion, theoretical best performance times are set by the product of the energy cost of the locomotion (i.e. the amount of metabolic energy spent to move over one unit of distance) and the maximal metabolic power (i.e. a . function of maximal oxygen uptake [VO2max] and maximal anaerobic capacity).[1,2] Thus, the energy cost of locomotion represents the efficiency of athletes and appears to contribute to the variation found in distance performance among top-level athletes. Endurance events such as triathlon or

marathon running are known to modify athletes’ biological constants and should have an influence on their efficiency. This has classically been shown to be important in sports performance, especially in events such as long-distance running, cycling or triathlon.[1-3] In competition events, the energy cost for a given power output is dependent on both the energy needed to overcome the external resistance (adenosine triphosphate) and the energy used in the production of external energy (internal energy). Consequently, the energy cost

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The Olympic distance triathlon involves successive swimming, cycling and running sessions; it begins with a swimming segment of 1500 m, followed by a 40-km cycling leg and concludes with a 10-km running leg. Given the variety of races during Olympic or World Cup events, these exercises are performed in various conditions of water temperature, road topography, surface and environmental settings.[9] Therefore, recent studies have highlighted a possible discrepancy between factors affecting efficiency during competition and those classically identified during experimental settings in laboratory. One of the main differences is related to the stability of power output in laboratory studies when compared with pacing strategies used during races, especially when competitive stakes are huge, as they are during the Olympics Games. The physiology of pacing during athletic events has only recently received full attention.[10] The pacing strategy is

% of total cycling time

1. Overview of the Strategic Aspects in Olympic Triathlon

defined as the within-race distribution of power output, speed or voluntary adjustments induced by athletes during cycling and running (e.g. voluntary change in cadence or speed). Pacing has recently been hypothesized to be an important factor involved in the mechanisms of human fatigue and can be considered as a strategy to avoid catastrophic failure in any peripheral physiological system.[11,12] Accordingly, pacing strategies have been described as a nonlinear dynamic system leading to particular metabolic or neuromuscular fatigue when compared with constant intensity exercise.[10,13-16] Recent studies have tried to describe the power output profile during road cycling[14,17] or during the cycle stage of the Beijing World Cup test event (24 Sep 2006) of the future Olympic triathlon in China 2008 (figure 1, Bernard et al., unpublished data). These results have highlighted, on the one hand, the stochastic aspect of power output during an Olympic triathlon and, on the other hand, the role of pacing strategies in fatigue appearance and decrease in efficiency. In recent studies focusing on factors affecting performance during an Olympic distance triathlon, the drafting position, power output production or cycling cadence selection have been reported to be the most common strategic factors used to explain changes in pacing strategies and performance over a swim-cycle-run combination.

<1

of locomotion could be improved by reducing external energy and/or internal energy or both.[4,5] In addition, many factors are known or hypothesized to influence the energy cost, such as environmental conditions, athlete’s profile (trained or elite level) and metabolic modifications (e.g. training status, fatigue). Thus, strategic aspects of the race that may affect metabolic demand and performance during long-duration events include energetics and biomechanical factors. During the last decade, many studies have attempted to identify these factors by analysing the relationship between metabolic and biomechanical factors with exercise duration during a specific Olympic event: the Olympic distance triathlon, which takes approximately 2 hours to complete and requires the use of three locomotion modes.[6-8] Therefore, the purpose of this review is to (i) review strategies to improve efficiency of the athlete during locomotion; and (ii) analyse the effects of these strategies on performance during an Olympic distance triathlon.

Exercise intensity zones Fig. 1. Percentage of total cycling time to the exercise intensity zones during each section of the triathlon distance World Cup in Beijing (24 Sep 2006). L = cycling lap; MAP = maximal aerobic power; VT = ventilatory threshold; - p < 0.05 vs L1, L2; * p < 0.05 vs L3, L4. Mean + SD.

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Improving Energetics in Long Distance Events

2. Benefits of Drafting in Swimming: Focus on Variables Conditioning Positive Effects Drafting while swimming front crawl, i.e. swimming directly behind or at the side of another swimmer, is mainly used in triathlon races or openwater swims. Drafting allows the swimmer to reduce the energy cost of swimming propulsion and hence gain time for swimming at maximal speed.[18] Hydrodynamic drag can be reduced when swimming in a drafting position. The effects of drafting during short swimming bouts have been widely studied in the recent literature.[19-21] The main factor of decreased body drag with drafting seems to be the depression made in the water by the lead swimmer.[20] This low pressure behind the lead swimmer decreases the pressure gradient from the front to the back of the following swimmer, hence facilitating his displacement. In submaximal conditions, precisely at an intensity of 95% of maximal speed over a 549-m swim, Basset et al.[19] showed that drafting affected the metabolic responses to swimming. Oxygen uptake was reduced by 8 – 12%, blood lactate concentration by 33 – 17%, and the rate of perceived exertion by 21 – 10%. The lower resistive body drag (passive drag) forces encountered by the swimmers at maximum speed are responsible for the observed metabolic change.[18] These forces were 13–26% lower than those for the lead swimmer, depending on the velocity of the individual swimmer. These authors showed specifically that swimming behind a leader resulted in an increase in swimming velocity (3.2%, i.e. a 20-m benefit over a 400-m race) and stroke length, and a reduction in blood lactate concentration and stroke frequency. They found that the gain in performance was related to the ability and the skinfold thickness of the swimmer, with faster and leaner swimmers achieving a greater gain. In this context, Chollet et al.[21] demonstrated that the performance increased from 1.34 m/sec to 1.39 m/sec when swimmers drafted the leader during a 400-m race. Moreover, the authors concluded that drafting also contributes to stabilization of the stroke parameters such as stroke frequency and stroke length during swimming. The distance adopted by the drafting in swimming appears to be a consistent parameter that ª 2008 Adis Data Information BV. All rights reserved.

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could be linked to overall swimming performance. Chatard et al.[18,20] showed that the optimum drafting position was in the 0- to 50-cm range behind another swimmer, although a significant reduced metabolic response persisted at distances of 100- and 150-cm. This result confirmed the average 60-cm distance spontaneously adopted by drafters in high-level triathlon (Millet et al.[22]). In triathlon, another parameter that is taken into consideration is the wearing of wetsuit. Delextrat et al.[23] demonstrated that the significant effect of drafting previously reported in the scientific literature was observed even though subjects were wearing a wetsuit. They showed a significant decrease in heart rate (7%) in drafting position during a 750-m race where the ‘draftees’ wear a wetsuit. It could be concluded that during triathlon events, where subjects are wearing wetsuits, drafting could either increase the reduction in metabolic load during swimming or allow triathletes to swim faster. In addition, Mollendorf et al.[24] evidenced the possibility that body suits which cover the torso and legs (i.e. as in triathlon) could reduce drag and improve the performance of swimmers. To conclude, several racing strategies have been developed by triathletes either to conserve energy for the swimming or for the cycling part of a triathlon. 3. Drafting in Swimming and Consequences on the Subsequent Cycling Event Research investigating the influence of swimming on subsequent cycling performance is somewhat limited.[23,25,26] However, despite the lack of experimental studies, recent reviews on triathlon determinants highlighted that the metabolic demand induced by swimming could have detrimental effects on subsequent cycling adaptations.[6] Recently, Delextrat et al.[23] have observed a significant decrease in cycling efficiency (17.5%) after a 750-m swim conducted at a sprint triathlon competition pace when compared with an isolated cycling bout. Actually, in an elite Olympic distance triathlon, the strategy of drafting during the cycling leg can influence the energy demands of this section, as well as during the swimming and Sports Med 2008; 38 (11)

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running sections.[6] It is well known that the start and first third of the swim leg are a major determinant of the final race result.[27] These authors reported that in an International Triathlon Union World Cup, the top performers in the overall triathlon were significantly faster in the first 400–500 m of the swim section. Moreover, the first 20 km of cycling has also been shown to have a large influence on the overall results, mostly linked to strategies employed during the race.[6] In a recent study, Delextrat et al.[23] demonstrated that the decrease in metabolic load associated with swimming in a drafting position involved two main modifications in physiological parameters during subsequent cycling. Firstly, oxygen uptake kinetics, at the onset of cycling, were significantly slowed when the prior swimming bout was performed in a drafting position (slower time constant) compared with swimming alone. Secondly, a significantly higher cycling efficiency (+4.8%), measured at steady-state level, was observed in the drafting condition compared with the isolated swim. This improvement in cycling efficiency could be mainly accounted for by the relatively lower swimming intensity, involving a lower state of fatigue in the muscles of the lower limbs at the beginning of the subsequent cycling session (figure 2). Consequently, the authors suggested that the increase in cycling efficiency could lead to an improvement in the overall performance during a triathlon. In addition to this study, a more recent

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experiment conducted by Bentley et al.[28] compared the effects of drafting or a reduction in exercise intensity during swimming on the power output sustained during a subsequent cycle time trial. They found that the power output maintained during a 20-minute time trial in cycling after a 400-m free-style swim is significantly increased when subjects performed the test in drafting conditions when compared with a non-drafting situation at the same velocity. Furthermore, in this previous study, performance in cycling after swimming with drafting at 100% of the all-out test velocity is similar to cycling after swimming at 90% of this speed in a non-drafting condition. Thus, they demonstrated that whilst swimming may affect cycling performance, drafting results in a similar performance response during cycling. This could have direct implications for training approach in triathlon and/or strategy during a World Cup triathlon event. In the same context of World Cup triathlon, Vleck et al.[27] showed that the position after the swim stage was strongly correlated to velocity measured at 222 m and 496 m. The overall finishing position in the Olympic distance triathlon was significantly correlated with the average swimming velocity (r = -0.52) and the position after the swim stage (r = 0.44). In addition, the authors recorded that the slower swimmers cycled significantly faster in the first 20 km of the cycle stage than the faster swimmers. This was reflected in the positions at the end of this stage, as the slower swimmers were able to benefit from a more sheltered position in the larger group of cyclists and therefore close the gap on the frontrunners. 4. Benefits of Drafting in Cycling: Focus on Variables Conditioning Positive Effects

160 140 120 1

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Fig. 2. Changes in heart rate during the last 5 minutes of the two swimming trials (reproduced from Delextrat et al.,[23] with permission). SAC = swimming alone condition; SDC = swimming with drafting condition. * p < 0.05 (significantly different).

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During individual road cycling events, it is possible to very accurately predict performance given knowledge of the mass of the system (bicycle and rider), its aerodynamic characteristics and the athlete’s physiological qualities.[29,30] During multiple cyclist events, riders have the opportunity to draft one another. In this context, the magnitude of the drafting effect in cycling can be impressive. Jeukendrup et al.[31] showed an Sports Med 2008; 38 (11)

Improving Energetics in Long Distance Events

average power output of only 98 W during a stage of the Tour de France, some 152 W less than is estimated for a rider performing alone.[8,31] McCole et al.[32] demonstrated that in a drafting . situation, a cyclist spares about 18% of VO2 at 32 km/h, and the benefit of drafting for a single cyclist at 37 and 40 km/h was greater (27%) than at 32 km/h. Recently, Edwards and Byrnes[33] hypothesized that leader drag area is an important determinant of the drafting effect in cycling. Therefore, they indicated a strong mean effect of leader drag area, whether that effect is expressed in terms of the drag coefficient or power output. In addition, they found that the ratio between drag area of a leader and the drag area of a drafter is strongly correlated with the drafting effect. 5. Drafting in Cycling and Consequences on the Subsequent Run Little is known about drafting in cycling and its influences on the following run during a triathlon. The first interesting finding was given by Hausswirth et al.,[34] indicating that drafting during the bike course of a triathlon (i.e. immediately after the swim leg) lowered both energy expenditure, heart rate and pulmonary ventilation values for a drafting distance of 0.2–0.5 m behind a lead cyclist. To our knowledge, drafting during the cycling leg of a triathlon has not been scientifically documented, because experiments have focused on simulated outdoor triathlon rather than triathlon competitions. Hausswirth et al.[34] demonstrated a . global reduction in VO2 (-14%), heart rate (-7.5%) and pulmonary ventilation (-30.8%) for the drafted cycle leg and for an average cycling speed of 39.5 km/h. When we compared these data with those of McCole et al.[32] (at a cycling speed of 40 km/h, the reduction in oxygen . uptake was about 27%), the differences in saved VO2 were explained by the likelihood of less efficient drafting during the initial phase (i.e. first 4 km) of the cycling section of the simulated outdoor triathlon, due to the residual negative effects of the swim stage.[34] Because of the common use of drafting in cycling during elite triathlon events (i.e. Olympic Games) and the various race strategies now employed, it seems important for triathletes to know the effects of ª 2008 Adis Data Information BV. All rights reserved.

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pacing up with another cyclist in order to save energy for the consecutive run. More recently, Hausswirth et al.[35] investigated the physiological responses of riding alternately or continuously behind another cyclist during a simulated indoor sprint distance triathlon. The authors showed a reduction of . 16.5% in VO2 and 11.4% in heart rate during the cycle leg when drafting continuously compared with alternate drafting. In association, they recorded a better 5-km running performance after the continuous-drafting cycle leg (+4.2%) compared with the running performance after the alternate-drafting cycle leg, indicating the practical benefit of adopting a constant drafting position for as long as possible during the cycling leg. 6. Drafting in Running: How Can Athletes Benefit? In 1926, Sargent[36] carried out the first detailed . study of the relation of VO2 and running speed. He solved the difficulties associated with the Douglas bag method by having his subjects run 120 yards (~110 m) while holding their breath. Expired gas was collected for 40 minutes after running, and the resting supine oxygen uptake was deducted from the total oxygen uptake to give the . VO2, and hence the energy requirement of . the work. The results seemed to show that the VO2 increased as the 3.8th power of velocity. Over 40 years later, Pugh[37] found that at a speed of 6 m/sec, 80% of the oxygen cost of meeting air resistance was eliminated by running close behind another runner. Unless some other adverse effect is present to cancel this advantage, an athlete should. be able to exceed the speed corresponding to his VO2max by up to 6% (7.5 · 0.80) by running behind a pace-maker or a faster competitor. . According to the relation of VO2 and. speed in track running found by Pugh,[37] the VO2 corresponding to a speed of 6 m/sec is 76 mL/min/kg, . and the speed corresponding to a 6% greater VO2 (i.e. 80.5 mL/min/kg) is 6.4 m/sec. This is the equivalent of a reduction in time for a 400-m lap from 66.6 to 62.5 sec. Track experience, however, suggests that in reality, athletes cannot run close enough to gain as much as advantage as this. . As presented in figure 3, the reduction in VO2 Sports Med 2008; 38 (11)

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v2 (m/sec) . Fig. 3. Oxygen intake (VO2) and the square of wind velocity (v2) for subjects running at 4.46 m/sec against varying wind velocities alone on the treadmill (not shielded) and behind another runner (shielded) [reproduced from Pugh,[37] with permission from Blackwell Publishing].

achieved by running behind another runner at 4.46 m/sec was 250 mL/min/kg; therefore, by run. ning close behind another runner, VO2 is 6.5% less than without shielding.[37] Thus, 80% of the energy cost of overcoming air resistance can be abolished by drafting in running. During the running stage of elite triathlon races, the top 50% of athletes used to run at a speed of 5.30 m/sec,[27] which is close to the speed where they could benefit from being sheltered behind another runner. Therefore, the effect of shielding is well known to athletes and team managers, they have regarded it as a positive perceived effect. Thus, especially during windy events, it would likely be advantageous to draft during the running leg of the race. The observation that this advantage has a physiological basis may enable elite triathletes to use it during the running stage with a greater tactical understanding than previously. 7. Benefits of Cadence Choice during Cycling: Focus on Variables Conditioning Positive Effects Additional cross-sectional studies have focused recently on the determination of pacing parameters that may be manipulated by triathletes during the cycle leg. In this case, the impact of cycling cadence during a cycle-run combination has received great attention from researchers ª 2008 Adis Data Information BV. All rights reserved.

and coaches.[6,34,39-41] In a simulated triathlon, Hausswirth et al.[34] first demonstrated an indirect effect of cadence upon subsequent running performance. In this study, triathletes selected a cadence of 95 rpm during the drafting condition compared with 89 rpm during the no-draft modality. It may be argued that the choice of a higher cadence (>90 rpm) associated with a decrease in force applied to the crank and/or electromyographic activity of lower muscle limb[42,43] contributes to the improvement of subsequent running performance. During constant-power laboratory testing, an apparent conflict is systematically observed between the energetically opti. mal cadence (EOC), i.e. the cadence at which VO2 is minimal, and the freely chosen cadence (FCC), i.e. the cadence that is spontaneously adopted during exercise.[42,44,45] These investigators have shown that the EOC may vary from 55 to 65 rpm, whereas FCC generally occurs between 80 and 95 rpm in endurancetrained runners, cyclists or recreational subjects. This suggests that the reduction of aerobic demand is not a key determinant of preferred cadence selection during cycling exercise, and several factors could be implicated. Therefore, it has been reported that the peak pedal force in cyclists reaches a minimum value for cadences of between 90 and 105 rpm, suggesting a strategy to reduce pedal force thanks to the adoption of high cadences.[42] These authors have speculated that this pedalling skill induced a decrease in muscle stress and influenced the preferred cadence selection. The selection of a high cadence classically reported during isolated cycling exercise has been also linked to additional biomechanical and physiological parameters such as lower extremity net joint moments, i.e. calculated by computer modelling,[45,46] muscle synchronization[47] or improved haemodynamic adjustments.[48] During prolonged exercise, studies highlighted the magnitude of the exercise duration on the choice of cycling cadence in triathletes. Constant FCC values (81–83 rpm) have been reported during a 30-minute cycle exercise, suggesting a relative stability of the movement pattern.[41,49] Conversely, earlier investigations showed a decrease in FCC towards the most economical Sports Med 2008; 38 (11)

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Cycling cadences (rpm)

100 95 90 85 80 75 70 65 5 30(a,d) 5 75(c) Exercise duration (min)

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Fig. 4. Variations in freely chosen cadence (FCC) with exercise duration in trained triathletes [(a) Brisswalter et al.,[49] (b) Lepers et al.,[50] (c) Vercruyssen et al.[41] and (d) Vercruyssen et al.[51]]. This indicates a significant decrease in FCC values with increasing exercise duration towards lower cycling cadences. Mean – SD.

cadence after 1 and 2 hours of cycling at a constant power output, indicating the relationship between cadence selection and neuromuscular fatigue appearance[50,51] (figure 4). 8. Cadence Choice during Cycling and Consequences on the Subsequent Run The effect of cadence on running performance has been recently investigated but limited data are available on this topic. During a laboratory-based investigation, Vercruyssen et al.[41] evidenced a relationship between the improvement of efficiency (i.e. decrease in energy cost) during running and the selection of prior cycling cadence at . an intensity of 80–85% VO2max. In this study, a reduction in oxygen demand was observed during an overall cycle-run combination (30 minutes + 15 minutes) when triathletes selected a cadence close to EOC (73 rpm). Conversely, the adoption of the FCC (81 rpm) or the theoretical mechanical optimal cadence (MOC, 90 rpm[52]) during . 30 minutes of cycling induced an increase in VO2 during the overall cycle-run combination. Several factors have been hypothesized to explain the observed differences between sessions, such as higher . cycling metabolic load (i.e. high percentage of VO2max sustained during the FCC and MOC conditions), changes in fibre recruitment patterns ª 2008 Adis Data Information BV. All rights reserved.

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or variations in haemodynamic adjustments during the cycle-run sessions. These results may be in line with those reported recently by the same group of researchers on the relationship between cycling cadence and running performance.[39] These investigators have shown an effect of cadence on the capacity to sustain an . of triathletes . elevated fraction of VO2max (FVO2max) during a . 3000-m run performance. The highest FVO2max values observed during running . were found after cycling at 60 rpm (i.e. 92% of VO2max) as compared with the other cycle-run combinations (i.e. . 84–87% of VO2max) where cadences were higher (80–100 rpm). Within this framework, Bernard et al.[39] indicated that the choice of a cadence close to 100 rpm was associated with an increased metabolic load during cycling, and highlighted that selection of high cadences before running was a poor strategy in terms of physiological benefits for triathletes. These findings suggest the possibility for triathletes to change cadence before the cycle-run transition in order to optimize the first minutes of subsequent running and, as a result, the overall performance. In this context, Vercruyssen et al.[41] recently demonstrated that the change in cadence selection during the last part of cycling leg markedly influences subsequent running time to exhaustion. In this study, the decrease in cadence (close to 75 rpm and the EOC classically reported in literature) during the last 10 minutes of the cycling leg improved the subsequent running time limit to exhaustion (894 seconds) compared with the running time limit (624 seconds) where triathletes increased their cadence before the cycle-run transition. This improvement in running performance (i.e. running time limit) consecutive to the selection of low cadence compared with high cadence may be linked to the reduced metabolic load reported during the final minutes of the cycling leg. Furthermore, the results previously reported seem to be contradictory, with anecdotal reports of competitive triathletes who prefer to select high pedalling cadence during the last minutes preceding the cycle-run transition.[6] Even if the selection of a low cadence appears to be linked to better metabolic responses in triathletes, future performance-based evaluations of different Sports Med 2008; 38 (11)

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cycle-run combinations are needed to establish an optimal cycle-run strategy relating to the cycling cadence manipulation and to pacing strategy adopted by triathletes. 9. Pacing Strategies Adopted during a Triathlon and Their Influences Focusing on the relative importance of swimming in triathlon performance, few authors concluded that the relationship between swimming . VO2max and overall triathlon performance did not exist,[53] or that it was weaker than the . relationship between running or cycling VO2max and overall performance. Indeed, triathlon performance has been found to correlate to swimming (r = -0.62), cycling (r = -0.87) and running . (r = -0.89) VO2max, but not to swimming economy (r = 0.21; not significant). The swim training for triathlon races is not much different to the training for an isolated swim race, but it has been suggested that certain factors influence swimming performance in triathlon, such as the propelling efficiency,[53] wetsuit advantage[54,55] and drafting skills,[21] which are specific to triathlon swimming. A recent study by Millet et al.[22] compared elite triathletes with elite swimmers at their highest swim velocities. They showed that triathletes increased their propulsive phases less than swimmers. Moreover, triathletes tended to increase their recovery phase, in contrast to swimmers, who reduced it. Moreover, the stroke length was lower for the triathletes than for the swimmers, while there was no difference in the stroke rate. The authors concluded that the shorter stroke length in triathletes confirmed that they have a lower propelling efficiency than swimmers.[56] Moreover, as widely suggested, it seems that stroke length is an appropriate and convenient criterion for evaluating technical improvement in triathletes. Anecdotal reports from triathletes highlight the transition from cycling to running as the tougher of the two transitions in a triathlon event. Hence, it is suggested that the format of the triathlon is advantageous towards athletes who can run well immediately after the cycling leg, which includes mostly a stochastic (i.e. variable) power output, ª 2008 Adis Data Information BV. All rights reserved.

under fatigue conditions.[57] However, the effects of metabolic responses and performance in constant- versus variable-intensity bouts on subsequent exercise have been examined, especially during a cycle-cycle combination in trained cyclists.[10,58,59] For instance, Palmer et al.[58] demonstrated that following 150 minutes of steadystate riding, the subsequent 20-km time trial (TT) performance was improved, compared with 150 minutes of stochastic exercise. However, it is important to note that this type of pacing strategy has been derived from cycling exercise conducted in laboratory settings or flat outdoor sessions, without any significant variability in topography or wind conditions.[60] In the context of a simulated cycling TT, Swain[61] predicted that the more a rider can vary power in parallel with changes in wind direction or gradient, the faster the ideal state of maintaining a constant speed is reached and, therefore, the greater the time saving. The author demonstrated that even modest (5% above or below a constant paced effort) variation in power would result in significant time savings. More recently, Atkinson et al.[14] investigated the acceptability of power variation during a cycling TT with simulated uphill and downhill sections. Results showed that finish times for the variable power trial (3370 seconds) was significantly faster than that for the constant power TT (3758 seconds). The authors concluded that some cyclists cannot fully adhere to a pacing strategy involving approximately –5% variation in mean power in parallel with gradient variation. Nevertheless, an important time saving can still result, even if a variable pacing strategy is only partially adopted during a hilly TT, so that no additional physiological strain is incurred. In the context of triathlon, the intensity in cycling can be constant when the cycling circuit is almost flat and when the competitors perform the cycling leg as an individual TT, specifically when drafting is not allowed. In contrast, a constant power output profile is not recorded when environmental conditions are modified because of hills, technical bike races or wind variations or when triathletes ride in a sheltered position (World Cup events, Olympic races), inducing very frequent changes in pace and intensity.[13] Sports Med 2008; 38 (11)

Improving Energetics in Long Distance Events

Only a few studies have examined the stride frequency and stride length during the running phase of an overground triathlon. Hausswirth et al.[62] showed the stride length to be reduced during a 30-minute triathlon run, from the first kilometre to the end; the pace was reduced from 14.5 km/h to 13.6 km/h. Although the stride length was shorter during the cycle-run transition than during a control run, the values were exactly the same for the two modalities at the end of the run. A more recent study examined changes associated with individual muscle function when changing from cycling to running;[63] and found that both the level and the duration of activation of several muscles (biceps femoris, vastus lateralis, vastus medialis and rectus femoris) were higher during the triathlon run than during a control run. The authors explained that the change from concentric muscle activation in cycling to stretch shortening muscle activation in running may be due to a decreased ability of the vastus lateralis and vastus medialis muscles to extend the knee in the flight phase of running, which highlights a need for specific training for the cycle-run transition. In addition, the cycle-run transition induced a more forward-leaning posture during the first kilometre of the run.[7] Therefore, specificity of training may allow appropriated coordination and active muscles to adapt efficiently to the transition between cycling and running without difficulties associated with the change in contraction type. The adoption of different running paces over the first kilometer of a triathlon run significantly influences the overall 10-km run performance. Accordingly, Hausswirth et al.[62] evidenced some interesting running strategies specifying that the choice of lower cadences, which generally result in lower stride rate and running speed values during the first kilometre,[39] could be a good strategy for improving running performance during an Olympic triathlon. In this study focusing on the role of different running strategies during an Olympic distance triathlon in elite triathletes, the first kilometre of running following cycling was performed at 5% faster, 5% slower or 10% slower than the average velocity recorded during the first kilometre of the isolated run. The remaining 9 km of each run was performed at a self-selected ª 2008 Adis Data Information BV. All rights reserved.

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pace. Compared with the 10-km isolated run performance, results demonstrated that the best running strategy following cycling was that in which the first kilometre was performed 5% slower (33.20 minutes for the 10-km run) than the average speed of the isolated run (33.48 minutes for the 10-km run). This underlines the need for a slower start to the run after cycling in order to keep the energy cost of running constant. Interestingly, a recent study[15] demonstrated that varying the power output from 5% to 15% of the mean power during a 20-km triathlon cycling leg resulted in decreased performance in the subsequent 5-km run compared with a constant power output cycling strategy. In contrast to studies focusing on cycling only,[60,61] this study suggested that, in the context of a triathlon, the alteration in running performance could be due to greater neuromuscular fatigue induced by stochastic power in cycling. All results concerning the cycle-run transition could be applied in training programmes where coaches are paying attention to the so called ‘Brick training’ (a bike-run or swim-run combination). 10. Conclusions This review has outlined potential parameters that may be relevant in elite triathletes and more generally in cyclists or marathon runners to improve overall Olympic performance. It has been shown that drafting position is the most prominent factor associated with successful performance. Other research has focused on the impact of power output production or cycling cadence during a cycle-run combination. Interestingly, cycling cadence choice also appears to be an important strategy for improving performance, especially during the last running stage, even if contradictory results make it difficult to establish a preferential pedalling strategy for the cycle leg. Recent research has suggested that the adaptation of triathletes must be considered as unique and relatively specific to the constraints activity (race profile, cycle-run transition, intensity and exercise duration). Specifically for long-duration Olympic events, research concerning pacing strategies is relatively recent and needs to be extended to Sports Med 2008; 38 (11)

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explain the appearance of specific fatigue phenomena and the possibility of maintaining or improving efficiency with exercise duration in such events. Acknowledgements No sources of funding were used to assist in the preparation of this review and the authors have no conflicts of interest directly relevant to its contents.

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endurance cycling in triathletes. J Sci Med Sport 2007; 9: 125-36 Vogt S, Heinrich L, Schumacher YO, et al. Power output during stage racing in professional road cycling. Med Science Sports Exerc 2006; 38: 147-51 Chatard JC, Chollet D, Millet GP. Performance and drag during drafting swimming in highly trained triathletes. Med Science Sports Exerc 1998; 30: 1276-80 Bassett DR, Flohr J, Duey WJ, et al. Metabolic responses to drafting during front crawl swimming. Med Science Sports Exerc 1991; 23: 744-7 Chatard JC, Wilson B. Drafting distance in swimming. Med Science Sports Exerc 2003; 35: 1176-81 Chollet D, Hue O, Auclair F, et al. The effects of drafting on stroking variations during swimming in elite male triathletes. Eur J Appl Physiol 2000; 82: 413-7 Millet GP, Chollet D, Chatard JC. Effects of drafting behind a two- or a six-beat kick swimmer in elite female triathletes. Eur J Appl Physiol 2000; 82: 465-71 Delextrat A, Tricot V, Bernard T, et al. Drafting during swimming improves efficiency during subsequent cycling. Med Sci Sports Exerc 2003; 35: 1612-9 Mollendorf JC, Termin II AC, Oppenheim E, et al. Effect of swim suit design on passive drag. Med Sci Sports Exerc 2004; 36: 1029-35 Kreider RB, Cundiff DJ, Hammet JB, et al. Effects of cycling on running performance in triathletes. Ann Sports Med 1988; 3: 220-5 Laursen PB, Rhodes EC, Langill RH. The effects of 3000-m swimming on subsequent 3-h cycling performance: implications for ultraendurance triathletes. Eur J Appl Physiol 2000; 83: 28-33 Vleck V, Bu¨rgi A, Bentley DJ. The consequences of swim, cycle, and run performance on overall result in elite Olympic distance triathlon. Int J Sports Med 2006; 27: 43-8 Bentley DJ, Libicz S, Jougla A, et al. The effects of exercise intensity or drafting during swimming on subsequent cycling performance in triathletes. J Sci Med Sport 2007; 10: 234-43 di Prampero PE. Cycling on earth, in space, on the moon. Eur J Appl Physiol 2000; 82: 345-60 Olds T. Modelling human locomotion: applications to cycling. Sports Med 2001; 31: 497-509 Jeukendrup AE, Craig NP, Hawley JA. The bioenergetics of world class cycling. J Sci Med Sport 2000; 3: 414-33 McCole SD, Claney K, Conte JC, et al. Energy expenditure during bicycling. J Appl Physiol 1990; 68: 748-53 Edwards AG, Byrnes WC. Aerodynamics characteristics as determinants of the drafting effect in cycling. Med Sci Sports Exerc 2007; 39: 170-6 Hausswirth C, Lehenaff D, Dreano P, et al. Effects of cycling alone or in a sheltered position on subsequent running performance during a triathlon. Med Sci Sports Exerc 1999; 31: 599-604 Hausswirth C, Vallier JM, Lehe´naff D, et al. Effect of two drafting modalities in cycling on running performance. Med Sci Sports Exerc 2001; 33: 385-90

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36. Sargent RM. The relation between oxygen requirement and speed in running. Proc R Soc 1926; 100: 10-22 37. Pugh LG. The influence of wind resistance in running and walking and the mechanical efficiency of work against horizontal or vertical forces. J Physiol 1971; 213: 255-76 38. Pugh LG. Oxygen intake in track and treadmill running with observations on the effect of air resistance. J Physiol 1970; 207: 823-35 39. Bernard T, Vercruyssen F, Grego F, et al. Effect of cycling cadence on subsequent 3-km running performance in well-trained triathletes. Br J Sports Med 2003; 37: 154-8 40. Gottshall JS, Palmer BM. The acute effects of prior cycling cadence on running performance and kinematics. Med Science Sports Exerc 2002; 34: 1518-22 41. Vercruyssen F, Brisswalter J, Hausswirth C. Influence of cycling cadence on subsequent running performance in triathletes. Med Science Sports Exerc 2002; 34: 530-6 42. Takaishi T, Ishida K, Katayama K, et al. Effect of cycling experience and pedal cadence on the near-infrared spectroscopy parameters. Med Science Sports Exerc 2002; 34: 2062-71 43. Takaishi T, Yasuda Y, Ono T, et al. Optimal pedaling rate estimated from neuromuscular fatigue for cyclists. Med Science Sports Exerc 1996; 28: 1492-7 44. Lucia A, Hoyos J, Chicharro JL. Preferred pedalling cadence in professional cycling. Med Science Sports Exerc 2001; 33: 1361-6 45. Marsh AP, Martin PE. Effect of cycling experience, aerobic power, and power output on preferred and most economical cycling cadences. Med Science Sports Exerc 1997; 29: 1225-32 46. Widrick JJ, Freedson PS, Hamill J. Effect of internal work on the calculation of optimal pedaling rates. Med Science Sports Exerc 1992; 24: 376-82 47. Bieuzen F, Lepers R, Vercruyssen F, et al. Muscle activation during cycling at different cadences: Effect of maximal strength capacity. J Electromyogr Kinesiol 2006; 20: 112-23 48. Gotshall RW, Bauer TA, Fahmer SL. Cycling cadence alters exercise hemodynamics. Int J Sports Med 1996; 17: 17-21 49. Brisswalter J, Hausswirth C, Smith D, et al. Energetically optimal cadence versus freely-chosen cadence during cycling: effect of exercise duration. Int J Sports Med 2000; 20: 1-5 50. Lepers R, Hausswirth C, Maffiuletti NA, et al. Evidence of neuromuscular fatigue after prolonged cycling exercise. Med Science Sports Exerc 2000; 32: 1880-6

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51. Vercruyssen F, Hausswirth C, Smith D, et al. Effect of exercise duration on optimal pedaling rate choice in triathletes. Can J Appl Physiol 2001; 26: 44-54 52. Neptune RR, Herzog W. The association between negative muscle work and pedaling rate. J Biomech 1999; 32: 1021-6 53. Kohrt WM, Morgan DW, Bates B, et al. Physiological responses of triathletes to maximal swimming, cycling and running. Med Sci Sports Exerc 1987; 19: 51-5 54. Chatard JC, Senegas X, Selles M, et al. wetsuit effect: a comparison between competitive swimmers and triathletes. Med Sci Sports Exerc 1995; 27: 580-6 55. Chatard JC, Millet GP. Effects of wetsuit use in swimming events. Sports Med 1996; 22: 70-5 56. Toussaint HM. Differences in propelling efficiency between competitive and triathlon swimmers. Med Sci Sports Exerc 1990; 22: 409-15 57. Williams KR. Conquering rubbery legs off the bike (part one). Triathlon Multisport 2000; 3: 16-7 58. Palmer GS, Noakes T, Hawley JA. Effects of steady-state versus stochastic exercise on subsequent cycling performance. Med Sci Sports Exerc 1997; 29: 684-7 59. Palmer GS, Borghouts LB, Noakes T, et al. Metabolic and performance responses to constant-load vs. variable-intensity exercise in trained cyclists. J Appl Physiol 1999; 87: 1186-96 60. Atkinson G, Brunskill A. Pacing strategies during a cycling time trial with simulated headwinds and tailwinds. Ergonomics 2000; 43: 1449-60 61. Swain DP. A model for optimizing cycling performance by varying power on hills and in wind. Med Sci Sports Exerc 1997; 29: 1104-8 62. Hausswirth C, Bernard T, Vallier JM, et al. Effect of different running strategies on running performance in Olympic distance triathlon. Proceedings of the 7th annual congress of the ECSS; 2002 Jul 24-28; Athens: 183 63. Heiden T, Burnett A. The effect of cycling on muscle activation in the running leg of an Olympic distance triathlon. Sports Biomech 2003; 2: 35-49

Correspondence: Prof. Jeanick Brisswalter, Sport Ergonomics and Performance Laboratory, EA 3162, University of Toulon-Var, Av. De l’Universite´, BP 20132, 83957 La Garde Cedex, France. E-mail: [email protected]

Sports Med 2008; 38 (11)

REVIEW ARTICLE

Sports Med 2008; 38 (11): 893-916 0112-1642/08/0011-0893/$48.00/0

ª 2008 Adis Data Information BV. All rights reserved.

The Importance of Sensory-Motor Control in Providing Core Stability Implications for Measurement and Training Jan Borghuis,1 At L. Hof 1 and Koen A.P.M. Lemmink 1,2 1 Center for Human Movement Sciences, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands 2 School of Sports Studies, Hanze University of Applied Sciences, Groningen, the Netherlands

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. About Core Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 The Core . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Core Stability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Important Structures in Maintaining Core Stability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Local and Global Muscle Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5 Hip Musculature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6 Stability versus Mobility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.7 Strength, Endurance and Sensory-Motor Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.8 Sensory-Motor Control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Core Stability, Athletic Performance and Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Core Stability and Athletic Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Core Stability and Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 The Role of the Hip Musculature in Injury Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Strength versus Endurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Spinal Instability Caused by Neuromuscular Imbalance in the Local Muscle System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6 Spinal Instability Caused by Neuromuscular Imbalance in the Global Muscle System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7 Sensory-Motor Control and Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Core Stability, Neuromuscular Core Control and Balance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Delayed Muscle Reflex Response in Patients with Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Neuromuscular Imbalance in Patients with Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Balance Performance in Relation to Core Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Relationship between Balance Performance and Neuromuscular Core Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Training Core Stability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Functional Training of Both the Local and Global Muscle System. . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Core Strengthening: Coordinative and Proprioceptive Training . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Swiss-Ball Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Measuring Core Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Measuring Core Strength and Endurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Measuring Neuromuscular Control and Coordination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions and Recommendations for Further Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Although the hip musculature is found to be very important in connecting the core to the lower extremities and in transferring forces from and to the core, it is proposed to leave the hip musculature out of consideration when talking about the concept of core stability. A low level of co-contraction of the trunk muscles is important for core stability. It provides a level of stiffness, which gives sufficient stability against minor perturbations. Next to this stiffness, direction-specific muscle reflex responses are also important in providing core stability, particularly when encountering sudden perturbations. It appears that most trunk muscles, both the local and global stabilization system, must work coherently to achieve core stability. The contributions of the various trunk muscles depend on the task being performed. In the search for a precise balance between the amount of stability and mobility, the role of sensory-motor control is much more important than the role of strength or endurance of the trunk muscles. The CNS creates a stable foundation for movement of the extremities through co-contraction of particular muscles. Appropriate muscle recruitment and timing is extremely important in providing core stability. No clear evidence has been found for a positive relationship between core stability and physical performance and more research in this area is needed. On the other hand, with respect to the relationship between core stability and injury, several studies have found an association between a decreased stability and a higher risk of sustaining a low back or knee injury. Subjects with such injuries have been shown to demonstrate impaired postural control, delayed muscle reflex responses following sudden trunk unloading and abnormal trunk muscle recruitment patterns. In addition, various relationships have been demonstrated between core stability, balance performance and activation characteristics of the trunk muscles. Most importantly, a significant correlation was found between poor balance performance in a sitting balance task and delayed firing of the trunk muscles during sudden perturbation. It was suggested that both phenomena are caused by proprioceptive deficits. The importance of sensory-motor control has implications for the development of measurement and training protocols. It has been shown that challenging propriocepsis during training activities, for example, by making use of unstable surfaces, leads to increased demands on trunk muscles, thereby improving core stability and balance. Various tests to directly or indirectly measure neuromuscular control and coordination have been developed and are discussed in the present article. Sitting balance performance and trunk muscle response times may be good indicators of core stability. In light of this, it would be interesting to quantify core stability using a sitting balance task, for example by making use of accelerometry. Further research is required to develop training programmes and evaluation methods that are suitable for various target groups.

Core stability is a hot issue in today’s medical world, especially in sport rehabilitation, but at the same time, it is still quite a vague concept ª 2008 Adis Data Information BV. All rights reserved.

about which there is much discussion. Questions are taken into consideration as to whether core stability is important with respect to injury Sports Med 2008; 38 (11)

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prevention of the back and the lower extremities and what effect core stability has on power and endurance during athletic performance. However, when talking about the concept of core stability, it is relevant to first have a common general definition, thereby assuring that the discussion surrounds one and the same concept. The purpose of the present article is to give an overview of the existing literature with respect to several issues related to core stability. There are various notions about the composition and functioning of the core. Several attempts to define core stability have been found in the literature. This article looks at the importance of core strength within the concept of core stability. An overview is given of the relevant body structures and tissues that are important in providing core stability with special attention to the muscular system. Furthermore, the role of strength, endurance and sensory-motor control is reviewed. In the third part of this article, literature findings will be discussed regarding the relationship between core stability on the one hand and athletic performance and injury on the other hand. The role of deficiencies in sensory-motor control with respect to clinical instability and lower extremity and low back injuries will be discussed in further detail. In the existing literature, core stability is often associated with the maintenance of balance, especially in measurement and training procedures. To clarify this relationship, an overview is given about the association between core stability, balance performance and the results of various studies in which electromyographic (EMG) measurements of the trunk muscles have been made during perturbation tasks. First, some studies are discussed in which muscle reaction times and muscle recruitment patterns have been investigated in patients with low back pain. Subsequently, the relationship between core stability and balance is taken into consideration and eventually an overview is presented about the correlations found between balance performance and EMG-measurement results. Section 4 of this review is mainly dedicated to the role of coordinative and proprioceptive training in enhancing core stability. Special focus ª 2008 Adis Data Information BV. All rights reserved.

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is given to the effects of exercises in which a Swiss ball is used as a training aid. Finally, we look at the current ways in which core stability is being measured. First, some issues are discussed with respect to the measurement of trunk muscle strength and endurance. Eventually, several tests will be considered that have been used to directly or indirectly measure neuromuscular control and coordination. PubMed was used to search for articles. Search terms included ‘core stability’, ‘trunk stability’, ‘lumbar spine stability’, ‘core strength’ and ‘neuromuscular core control’ and these were combined with terms such as ‘measurement’ or ‘training’. Various review articles were found containing useful references. The present article is based on a selection of the most valuable and relevant of these articles. 1. About Core Stability The term ‘core stability’ has received a lot of attention, especially in the past few years. It is stated that core stability is a key component in the training programmes of individuals who are aiming to improve their health and physical fitness, but core stability is also an important concept in clinical rehabilitation and in the training of competitive athletes.[1] 1.1 The Core

Particular attention has been paid to the core because it serves as the centre of the functional kinetic chain. The core is seen as a muscular corset that works as a unit to stabilize the body and in particular the spine, both with and without limb movement.[2] In the alternative medicine world, the core has been referred to as the ‘powerhouse’, the foundation or engine of all limb movement.[2] Kibler et al.[3] also stressed the importance of the core in providing local strength and balance, in decreasing back injury and in maximizing force control. The core of the body includes both passive and active structures: the passive structures of the thoracolumbar spine and pelvis and the active contributions of the trunk musculature.[4] Sports Med 2008; 38 (11)

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Akuthota and Nadler[2] described the core as a box with the abdominals in the front, the paraspinals and gluteals in the back, the diaphragm as the roof and the pelvic floor and hip girdle musculature as the bottom. Kibler et al.[3] state that the musculoskeletal core of the body includes the spine, hips and pelvis, abdominal structures and also the proximal lower limb. According to them, the core musculature includes the muscles of the trunk and pelvis.[3] These muscles are responsible for the maintenance of stability of the spine and pelvis and help in the generation and transfer of energy from large to small body parts during many sports activities. So, in addition to its stabilizing function, the core musculature also has a mobilizing function.[3] 1.2 Core Stability

There is no single universally accepted definition of core stability. Panjabi[5] presented a conceptualization of core stability that is based on three subsystems: the passive spinal column, active spinal muscles and a neural control unit. Based on this conceptualization, Liemohn et al.[1] defined core stability as ‘‘the functional integration of the passive spinal column, active spinal muscles and the neural control unit in a manner that allows the individual to maintain the intervertebral neutral zones within physiological limits, while performing activities of daily living.’’ Kibler et al.[3] defined core stability as ‘‘the ability to control the position and motion of the trunk over the pelvis, thereby allowing optimum production, transfer and control of force and motion to the terminal segment in integrated athletic, kinetic chain activities.’’ Leetun et al.[6] stressed the importance of the passive structures to a lesser degree and stated that core stability can be seen as the product of motor control and muscular capacity of the lumbo-pelvic-hip complex. This definition stresses the importance of coordination in addition to core strength and endurance. Although the terms core stability and core strength are sometimes used interchangeably, core strength is just one part of the core stability concept and so the term ‘core strength’ is subsumed within the concept of core stability. ª 2008 Adis Data Information BV. All rights reserved.

McGill and Cholewicki[7] formulated a biomechanical foundation for stability that gives useful insights in the complex interactions that are involved when stabilizing the core. Their theory was based on and elaborated on the work of Bergmark,[8] who mathematically formalized the concepts of energy wells, stiffness and stability. According to McGill and Cholewicki,[7] the foundation of core stability begins with the concept of potential energy. For musculoskeletal application, the focus is mainly on elastic potential energy. Elastic bodies possess potential energy by virtue of their elastic deformation under load and this elastic energy is recovered when the load is removed.[7] The greater the stiffness, the more stable the structure. Thus, stiffness creates stability.[9] Joint stiffness increases rapidly and nonlinearly with muscle activation, so that very modest levels of muscle activity create sufficiently stiff and stable joints.[9] Furthermore, joints possess inherent joint stiffness through their ligaments and other capsular structures. These structures contribute to stiffness, which increases towards the end range of joint motion.[7] All stabilizing musculature must work coherently to achieve stability.[7] For the purpose of their study, Zazulak et al.[4,10] developed a more operational definition. They defined core stability as ‘‘the body’s ability to maintain or resume an equilibrium position of the trunk after perturbation.’’ It should be considered here that, while the focus of McGill and Cholewicki[7] is mainly on the anticipating reaction of the core structures during small, expected perturbations, Zazulak et al.[4,10] also assume greater, unexpected disturbances of the core, in which the creation of stiffness does not suffice to maintain stability. If the initial spine stability is insufficient in relation to the external load applied by a perturbation, a fast and strong reflex response can compensate, in order to constrain trunk motion within a safe boundary. Such a direction-specific muscle reflex response may be crucial in preventing large intervertebral displacements or buckling of the spine and subsequent damage of soft tissues under sudden loading conditions.[11] Sports Med 2008; 38 (11)

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1.3 Important Structures in Maintaining Core Stability

Lumbar spine stability is provided by bone, disc, ligaments and muscle restraints.[12] As noted above (section 1.2), stability of the lumbar spine requires both passive stiffness, through the osseous and ligamentous structures and active stiffness, through muscles.[2] If any of the active or passive components are impaired in function, instability of the lumbar spine may occur. It has been shown that the musculature is most important in maintaining spinal stability under various conditions.[12] Panjabi[5] suggested that muscle activity is used to compensate for a loss of passive stability. It has been shown that muscles can contribute to stability of the trunk through co-contraction.[13] Healthy subjects increase co-contraction in response to conditions that threaten spinal stability. This adaptation is triggered by information from both mechanoreceptors and nociceptors.[13] Co-contraction further connects the stability of the upper and lower extremities via the abdominal fascial system. This effect becomes particularly important in overhead athletes, because the created stable connection acts as a torque-counter torque of diagonally related muscles during throwing.[2] To acquire this co-contraction, precise neural input and output are needed. Arokoski et al.[14] identified that the stability of the spine was increased with either increased flexor-extensor muscle coactivation or increased intra-abdominal pressure. In the temporal sequence of many athletic tasks, core muscle activity precedes lower extremity muscle activity. Hodges and Richardson,[15] for example, demonstrated that trunk muscle activity often occurs before the activity of the lower extremity musculature. This implies that the CNS creates a stable foundation for movement of the lower extremities through co-contraction of particular muscles.[10] Kavcic et al.[16] conducted a systematic biomechanical analysis in order to assess the potential stabilizing role of individual lumbar muscles. This study showed that, when loads are applied to the spine, there is an integration of the different muscles in order to maintain spinal stability ª 2008 Adis Data Information BV. All rights reserved.

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and these control patterns change as the spine loading patterns change.[16] The same result was found by means of biomechanical analysis conducted by Cholewicki and McGill[17] and Cholewicki and VanVliet,[18] who suggested that no single muscle possesses a dominant responsibility in providing lumbar spine stability. Generally, those muscles that were antagonist to the dominant moment of the task were most effective at increasing stability.[16] It appears that most trunk muscles are important in providing core stability, their importance depending on the activity being performed.[9] These include muscles that attach directly to the vertebrae: the uni-segmental multifidus muscles and multi-segmented quadratus lumborum and longissimus, and muscles that do not: iliocostalis and the abdominal wall. Across the various trunk muscles, the mechanical advantage to provide stability to the lumbar spine varies. It should be born in mind that this variety is functional. This can be illustrated by the example of a long-guyed mast. Guy wires, wires running from the top and a few levels below to the ground, are needed to keep the mast upright, but the mast should also have sufficient stiffness by itself to prevent buckling. In the back, these functions are provided by the global stabilization system (GSS) and local stabilization system (LSS), respectively. 1.4 Local and Global Muscle Systems

Comerford and Mottram[19] stated that all muscles have the ability to concentrically shorten and accelerate motion for mobility function, to isometrically hold or eccentrically lengthen and decelerate motion for stability function and to provide afferent proprioceptive feedback to the CNS for regulation and coordination of muscle function. Bergmark[8] proposed a classification scheme that groups core muscles into either the GSS or the LSS. The larger muscles of the trunk are the chief contributors to the GSS and the smaller muscles are the main contributors to the LSS. The LSS plays a major role in the coordination and control of motion segments, whereas the muscles of the GSS, which have Sports Med 2008; 38 (11)

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larger masses and longer moment arms of force, provide more forceful movements.[1] The LSS muscles are closer to the spinal column and thus can provide varying degrees of segmental control. For example, the intertransversarii mediales, interspinales and rotators are very close to the centre of rotation of the spinal segments. Their high density of muscle spindles and their very small physiological cross-sectional area suggests that they may act primarily as position transducers of the spinal column.[20] Following the work of Bergmark,[8] Comerford and Mottram[19] have also proposed a classification system for muscle function. They have characterized muscles as local stabilizers, global stabilizers and global mobilizers. The function of the local muscle system is to provide sufficient segmental stability to the spine, whereas the global muscle system provides general trunk stabilization and enables the static and dynamic work necessary for daily living and sport activities.[21] A symmetrical activation of the local muscles has been shown during the performance of low load, asymmetric lifting tasks, which suggests that these muscles play a stabilizing role during these activities. The global muscles, however, show asymmetric patterns of activation during the same tasks, supporting their role of global stabilizers and prime movers.[21] It has been identified that the multifidus, transversus abdominis and the internal obliques are part of the local stabilizing system, whereas the longissimus thoracis, rectus abdominis and external obliques constitute a part of the global stabilizing system.[21] Recent work has focused on the functional contribution of different trunk muscles to postural stabilization of the lumbar spine as well as their respective changes in the presence of acute and chronic pain. Although the sensory-motor control of spinal stability is provided in a mutual interaction among all muscles of the trunk, Ebenbichler et al.[12] described four major functional groups of muscles that contribute via different mechanisms to the postural stabilization of the spine: (i) local, paravertebral muscles that directly stabilize the segments of the spine; (ii) global, polysegmental, paravertebral muscles that balance external loads to minimize the ª 2008 Adis Data Information BV. All rights reserved.

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resulting forces on the spine; (iii) muscles that contribute to pressure facilitation within the abdominal cavity, thereby providing global stabilization of the spine; and (iv) muscles that facilitate the pressure within the fascia tube system of the back.[12] Cholewicki and VanVliet[18] reported that all trunk muscles, including abdominal as well as back musculature, contribute to core stability. The relative contributions of each muscle group continually change throughout an athletic task.[10] The abdominals serve as a vital component of the core. In particular, the transversus abdominis has received a lot of attention.[2] Contracting the transversus abdominis increases intra-abdominal pressure and tensions the thoracolumbar fascia. The thoracolumbar fascia is an important structure that connects the lower limbs (via the gluteus maximus) to the upper limbs (via the latissimus dorsi). It helps to form a ‘hoop’ around the abdomen, consisting of the fascia posteriorly, the abdominal fascia anteriorly and the oblique muscles laterally.[3] This way, a stabilizing corset effect is created. Together, the internal oblique, external oblique and transversus abdominis increase the intra-abdominal pressure inside the hoop formed via the thoracolumbar fascia, thus creating functional stability of the lumbar spine.[2] Contractions that increase intraabdominal pressure occur before initiation of large segment movement of the upper limbs.[3] In this manner, the spine is stabilized before limb movements occur, thereby allowing the limbs to have a stable base for motion and muscle activation. Thus, abdominal muscle contractions help in creating a rigid cylinder, thereby enhancing stiffness of the lumbar spine. It is also important to note that the rectus abdominis and oblique abdominals are activated in directionspecific patterns with respect to limb movements, thus providing postural support before limb movements.[3] According to Ebenbichler et al.,[12] the back muscles are clearly divided into two major groups: (i) the deep muscles of the lumbar spine that span one or a few segments including the multifidus muscle, the musculi rotatores lumborum, musculi interspinales and musculi Sports Med 2008; 38 (11)

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intertransversarii mediales and laterales; and (ii) the long erector spinae muscles that span many segments.[12] These two distinct functional muscle groups have large differences in innervation, which indicates significant functional differences. The stabilizing role of the paravertebral muscles aims mainly at protecting the articular structures, discs and ligaments from excessive bending, strains and injury.[12] According to Bergmark,[8] the role of the long, multisegmental back muscles is to provide general trunk stabilization and to balance external loads, thereby helping to unload the spinal segments. 1.5 Hip Musculature

At the opposite end of the trunk component of the core muscles are the pelvic floor muscles. Most of the prime mover muscles for the distal segments (latissimus dorsi, pectoralis major, hamstrings, quadriceps and iliopsoas) attach to the core via the pelvis and spine. Most of the major stabilizing muscles for the extremities (upper and lower trapezius, hip rotators and glutei) also attach to the core.[3] Because of the difficulty in directly assessing these muscles, they are often neglected or ignored with respect to musculoskeletal rehabilitation. The glutei are stabilizers of the trunk over the planted leg and provide power for forward leg movements.[3] The hip musculature plays a significant role within the kinetic chain, particularly for all ambulatory activities, in stabilization of the trunk and pelvis and in transferring force from the lower extremities to the pelvis and spine.[2] Although some authors[2,3] include the glutei as part of the core, being an integral part of core functioning, in the present article these muscles are seen as connections between the core and the lower extremities. Kibler et al.[3] stated that the glutei, as major stabilizing muscles for the extremities, attach to the core, implying that they do not constitute part of the core. 1.6 Stability versus Mobility [3]

According to Kibler et al., core muscle activity is best understood as the pre-programmed integration of local, single-joint muscles and ª 2008 Adis Data Information BV. All rights reserved.

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multi-joint muscles to provide stability and produce motion. This integrated core muscle activity results in proximal stability for distal mobility.[3] There is a proximal to distal patterning of force generation and a proximal to distal patterning in the creation of interactive moments that move and protect distal joints. Interactive moments are moments at joints that are created by motion and position of adjacent body segments.[3] They are developed in the central body segments. Interactive moments are important for developing proper force at distal joints and for creating relative bony positions that minimize internal loads at the joint.[3] Anderson and Behm[21] stated that much is known about how muscles maintain static equilibrium, but little is known about how they maintain dynamic balance when exerting an external force. Exerting external forces while attempting to maintain dynamic balance forms the base of success in the majority of sports and it is a necessity in the activities of daily living.[21] The cost of coping with instability is an increase in co-contractions, which results in a decrease in external force. However, in many instances, the task could not be performed without this coactivation.[21] Thus, this stabilization process consists of establishing active muscular constraints to minimize the degrees of freedom within one or several joints and results in stabilization of the excessive mobility of the extremities.[21] ‘Sufficient stability’ is both a complex concept and a desirable objective for which optimal balance between stability and mobility is required. However, the objective is constrained by the need for a modest amount of extra stability to form a margin of safety, but not so much as to compromise the spine with the additional load.[9] The art, especially for athletes, is to enhance mobility, while at the same time preserving sufficient stability. 1.7 Strength, Endurance and Sensory-Motor Control

Cholewicki and McGill[17] demonstrated that, in most persons, sufficient stability of the lumbar spine is achieved with very modest levels of co-activation of the paraspinal and abdominal Sports Med 2008; 38 (11)

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muscles. Thus, maintaining sufficient stability when performing tasks, particularly the tasks of daily living, is not compromised by insufficient muscle strength.[9] It has been shown that only a very small increase in activation of the abdominal muscles is required to stiffen the spinal segments (5% of maximal voluntary contraction for activities of daily living and 10% of maximal voluntary contraction for rigorous activity).[3] Furthermore, it has been suggested that back muscle contractions as low as 25% of maximal voluntary contraction are able to provide maximal joint stiffness.[22] A low percentage of maximal voluntary isometric contraction from the trunk musculature thus stabilizes the spine during normal movements. This implies that, alongside muscle strength, muscular endurance and, in particular, sensory-motor control are important aspects in providing sufficient core stability.[21] For example, the trunk flexor-to-extensor ratio may be as or more important than absolute strength and endurance, because this ratio has been shown to be abnormal in people with back pain.[23] 1.8 Sensory-Motor Control

In the last few decades, there has been an increasing awareness of the importance of the specialized and integrated action of the muscle system in maintaining stability and optimal function of the movement system. Efficient movement function and the maintenance of balance during dynamic tasks are more complex than merely adequate force production from the muscles. The muscle actions must be precisely coordinated to occur at the right time, for the correct duration and with the right combination of forces.[24] This coordinated action occurs within groups of synergistically acting muscles and is also important in the interactions between agonist and antagonist muscles. It requires sensory, biomechanical and motor-processing strategies along with learned responses from previous experience and anticipation of change.[24] A primary sensory mechanism for motor control is proprioception from the muscles. Gandevia et al.[25] stated that proprioception relates to three key sensations, namely sensation of position and movement of ª 2008 Adis Data Information BV. All rights reserved.

the joints, sensation of the perceived timing of muscle contraction and sensation of force, effort and heaviness of workload. It is important to note that the dynamic stability of the body, or any specific joint such as the knee, depends on neuromuscular control of the displacement of all contributing body segments during movement.[10] Core stability is related to the body’s ability to control the trunk in response to internal and external disturbances. These include forces generated from distal body segments as well as forces generated from expected or unexpected perturbations.[10] When a limb is moved, reactive forces are imposed on the spine acting in parallel and opposing those producing the movement.[12] Due to its multi-segmental nature and the requirement for muscle contraction to provide stability of the spine, the spine is particularly prone to the effect of these reactive forces. This indicates the importance of muscular control of the spine during limb movement.[12] Radebold et al.[26] stated that, in general, there is a combination of three levels of motor control (spinal reflex, brain stem balance, and cognitive programming) that produces appropriate muscle responses. The first one, the spinal reflex pathway, uses proprioceptive input from muscle spindles and Golgi tendon organs. For the automatic control of the motion segment, the presence of a ligamento-muscular reflex has been proposed.[12] The g-spindle system facilitates the a-motor neurons that control the slow twitch muscle fibres. The second level of motor control, the brain stem pathway, coordinates vestibular and visual input, thereby using proprioception from joint receptors.[26] Cognitive programming is based on stored central commands, which lead to voluntary adjustments.[26] Pre-programmed muscle activations result in so-called anticipatory postural adjustments.[3] These adjustments position the body to withstand the perturbations to balance created by the forces of actions such as kicking, throwing or running. Ebenbichler et al.[12] found that, when reactive forces due to limb movement challenged the stability of the trunk, some muscles contracted before the agonist limb muscle to compensate for the perturbing effect on posture. The anticipatory postural adjustments Sports Med 2008; 38 (11)

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create the proximal stability for distal mobility, as mentioned earlier (section 1.6). The muscle activations also create the interactive moments that develop and control forces and loads at joints.[3] Ebenbichler et al.[12] wrote about the presence of two parallel systems in the control of voluntary movements, one to control the intended voluntary element of the movement and one to initiate corrective forces necessary for maintaining equilibrium. It has been shown that there exists an inverse relationship between the length of the voluntary reaction time and the degree of postural stability in a certain situation.[12] A shorter reaction time for a specific task implies an increase in the postural stability. Findings from studies on trunk motor control demonstrated that the CNS immediately interrupts an ongoing voluntary motor programme to prioritize the postural control programme.[12] So, from these results, it can be concluded that appropriate muscle recruitment and timing is extremely important in the control of spine equilibrium and mechanical stability. 2. Core Stability, Athletic Performance and Injury In an article by Leetun et al.,[6] it was stated that core stability has an important role in injury prevention. Decreased lumbo-pelvic stability has been suggested to be associated with a higher occurrence of lower extremity injuries, particularly in females. This highlights the importance of proximal stabilization for lower extremity injury prevention. In addition, Anderson and Behm[21] suggested that a lack of trunk stabilization may also be a major contributor to the occurrence of low back pain. 2.1 Core Stability and Athletic Performance

Besides its local functions of stability and force generation, core activity is involved in almost all extremity activities such as running, kicking and throwing. Since the core is central to almost all kinetic chains in sports activities, control of core strength, balance and motion will maximize ª 2008 Adis Data Information BV. All rights reserved.

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all kinetic chains of upper and lower extremity function.[3] A few studies have been found that investigated whether improved core stability is associated with better physical performance. Stanton et al.[27] did not find a positive relationship between core stability and running performance as measured by maximal oxygen uptake or running economy, nor did they find an improved posture during treadmill running to volitional exhaustion with increased core stability. In addition, Tse et al.[28] found no increased functional performance in college-aged rowers after exposing them to an 8-week core endurance training programme. Considering the wide variety of movements associated with various sport activities, athletes must possess sufficient strength in hip and trunk muscles to provide stability in all three planes of motion.[6] More and more, scientists are including assessment of joint mechanics proximal and distal to the sites where injuries tend to occur. This is because of the closed chain nature of athletic activities. Motion at one segment will influence that of all other segments in the chain. However, the influence of proximal stability on lower extremity structure and pathology remains largely unknown.[6] Given the wide range of individuals and physical demands, questions remain as to what is the optimal balance between stability, motion facilitation and moment generation. And there are questions about how much muscular co-contraction is necessary to achieve stability and how it is best achieved.[9] 2.2 Core Stability and Injuries

Zazulak et al.[4] showed that proprioceptive deficits in the body’s core may contribute to decreased active neuromuscular control of the lower extremity, which may lead to valgus angulation and increased strain on the ligaments of the knee. Such findings, in addition to years of empirical evidence, have led to the suggestion that the knee may be a victim of core instability with respect to lower extremity stability and alignment during athletic movements.[6] In particular, in reference to anterior cruciate ligament injuries, Sports Med 2008; 38 (11)

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Ireland[29] described a so-called ‘position of no return’ that is characterized by hip adduction and internal rotation, which in turn leads to knee valgus and tibial external rotation. In addition, the same alignment tendency seems to be related to repetitive injuries such as patellofemoral pain syndrome and iliotibial band friction syndrome.[6] With respect to direct injuries of the body’s core, Nadler et al.[30] noted that athletes with acquired ligamentous injuries or lower extremity overuse were significantly more likely to require treatment for low back pain during the following year. In addition, various other factors have been shown to be associated with low back pain, under which are poor muscle endurance, altered muscle firing rates and muscular imbalance.[31] The occurrence of low back pain in an athletic population has been well documented in various sports, including football, golf, gymnastics, running, soccer, tennis and volleyball. Between 5% and 15% of all athletic injuries consist of low back pain.[32] Most sport injuries related to the lumbar spine are soft tissue injuries such as muscle strains, ligament sprains and intervertebral disc injuries.[32] These injuries often prevent the athlete from regular training and competition. Moreover, low back injuries have become an increasing problem, especially in relation to recreational activities with high demands on the back such as racquet sports, golf, handball, baseball, volleyball or rowing. In amateur athletes, these injuries often mean an end to those sporting activities and a prolonged disability to work.[33] 2.3 The Role of the Hip Musculature in Injury Occurrence

Some authors, who considered the hip musculature to be part of the body’s core, have investigated several characteristics of the hip muscles in relation to the occurrence of lower extremity or low back injuries. Some of their results are discussed below. In people with lower extremity instability or low back pain, poor endurance and delayed firing of the hip extensor (gluteus maximus) and ª 2008 Adis Data Information BV. All rights reserved.

abductor (gluteus medius) muscles have been identified.[31] With regard to muscular influences on low back pain, the hip musculature plays a significant role in transferring forces from the lower extremity towards the spine and thus may influence the development of low back injuries.[34] With respect to knee injuries, weak hip muscles are a common finding associated with knee injury. For example, weak hip abductors and tight hip flexors are seen in association with anterior knee pain.[3] Leetun et al.[6] have conducted a prospective study in which core stability measures were compared between athletes who reported an injury during their season versus those who did not. They looked for strength measures that could be used to identify athletes at risk for lower extremity injury. It was found that athletes who sustained an injury over the course of a season displayed significantly less hip abduction and external rotation strength than uninjured athletes.[6] Hip external rotation weakness most closely predicted injury status. These results are in accordance with the above described findings by Ireland,[29] who showed that hip abductors and external rotators play an important role in the alignment of the lower extremities. They assist in the prevention of movement into hip adduction and internal rotation during single limb support. However, as Leetun et al.[6] also argued themselves, hip external rotation strength is only one element of core stability and other aspects not included in the study may also have predicted the occurrence of lower extremity injury, especially because of the low coefficient of determination that was found for the hip external rotation strength. 2.4 Strength versus Endurance

In section 1 of this article, it has been shown that besides muscular strength, endurance and especially sensory-motor control are very important aspects in providing sufficient core stability. Let us first have a look at the endurance aspect. Ebenbichler et al.[12] stated that decreased trunk muscle extensor strength has often been associated with low back pain, but also back Sports Med 2008; 38 (11)

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muscle endurance appears to be reduced in patients with acute and chronic low back pain. McGill et al.[35] suggested that trunk muscle endurance is of greater importance in the prevention of low back pain than the ability of these muscles to generate force. In agreement with this suggestion, the endurance of the trunk extensors has been found to predict the occurrence of low back pain in 30- to 60-year-old adults.[6] However, it has to be said that the amount of muscle activation needed to ensure sufficient stability depends on the task.[35] Generally, for most tasks of daily living, very modest levels of abdominal wall co-contraction are sufficient. But if a joint has lost passive stiffness due to damage, more co-contraction is needed to compensate for the deficiency. Besides, when encountering unpredictable activities such as a sudden load to the spine, a fall or quick movements, a strength reserve is needed. In sport activities and during heavy physical work, there are increased demands on both strength and endurance.[36] However, according to McGill,[9] a review of the evidence suggests that greater ranges of spine motion are associated with increased risk of future problems and that endurance, more than strength, is related to reduced symptoms. 2.5 Spinal Instability Caused by Neuromuscular Imbalance in the Local Muscle System

In section 1 of the present article, a distinction between the local and the global muscle system has been observed. Dysfunction of movement around a joint can be a local or a global problem,[8] although both frequently occur together. Local problems can be caused by a dysfunction of the recruitment and motor control of the deep segmental stability system resulting in poor control of the neutral joint position.[36,37] The motor recruitment deficits present in two ways, namely altered patterns of recruitment and altered timing (a delay in muscle response time). Panjabi[38] described instability of a joint or motion segment in terms of a lack of dynamic muscle ª 2008 Adis Data Information BV. All rights reserved.

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control of the neutral zone, resulting in an abnormal increase in the range of motion. He defined the neutral zone as the range of intervertebral motion within which there is minimal internal resistance.[38] It is hypothesized that changes in a spinal segment that allow for excessive motion cause poor spinal stability and back pain. Structural changes that contribute to this instability are, among other things, disc disease, muscular changes such as weakness and poor endurance and ineffective neural control.[39] With respect to muscular changes, a significant reduction of cross-sectional area has been demonstrated in various local muscles, which is supposed to be associated with either failure of normal recruitment or with atrophy of the muscle.[24] Excessive motion of the lumbar segment results in the loss of sensory-motor control in a spine’s segment neutral zone. So an increased neutral zone has been suggested as an indicator of clinical instability, although no objective quantitative measurements for clinical use are currently available to assess this indicator.[12] To maintain mechanical stability of the lumbar spine, compensation is required by the trunk musculature. It has been shown that effective muscle control can return the neutral zone within physiological limits.[12] 2.6 Spinal Instability Caused by Neuromuscular Imbalance in the Global Muscle System

So far, we have only considered neuromuscular dysfunctions in the local muscle system, but functional stability is dependent on integrated function of both the local and global muscles. Mechanical spinal stability dysfunction can occur in the form of segmental (articular) or multi-segmental (myofascial) dysfunction. These dysfunctions present as combinations of restriction of normal motion and compensations to maintain function.[19] The role of the global spinal muscles is to control range of movement and alignment. Dysfunction of these muscles is caused by an imbalance in recruitment and length between the mono-articular stability muscles and the Sports Med 2008; 38 (11)

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bi-articular mobility muscles.[24] Comerford and Mottram[24] noted that there are many clinically consistent neuromuscular imbalances between synergistic and antagonistic muscles. These are characterized by the early and dominant recruitment of the multi-articular mobilizing trunk muscles, while the mono-articular stabilizing synergist recruitment is delayed or these muscles lack efficiency in their shortening capacity. This imbalance can result in abnormal over-pull and under-pull by the muscles around a motion segment, so that there is give (excessive joint motion) in the direction of over-activity and restriction (a loss of joint motion) in the direction of the less active global muscles.[19,24] The result of this faulty movement is abnormal accessory glides, which increase micro-trauma in the tissues around the joint, leading to dysfunction and pain.[19] In the normal functioning musculature, there exist complex motor control processes that regulate relative stiffness or flexibility in linked multi-chain movements.[24] The movement system has a great ability to adapt to changes. When significant restriction of motion occurs at a joint, the body will attempt to maintain function at all costs. To achieve this, some other joint or muscle must compensate by increasing relative mobility, which often results in tissue damage.[24] In summary, dysfunction in the global system presents in three interrelated forms, namely length-associated change related to muscle function, imbalance in recruitment between synergistic and antagonistic muscles and direction-dependent relative stiffness and compensation. 2.7 Sensory-Motor Control and Injuries

Now that we have seen the importance of sensory-motor control in providing stability, let us consider what is known about the relationship between deficient core neuromuscular control and the occurrence of injuries. In all activities of daily living, a human body is moved through three dimensions at differing velocities while experiencing varying torques and forces. Especially in sport activities, great demands are placed on the strength, endurance and coordination of the system. An inefficient ª 2008 Adis Data Information BV. All rights reserved.

neuromuscular system may not adapt well to these demands, resulting in impaired performance or even injury.[21] We have seen that spinal muscles provide stability and that muscle recruitment patterns significantly affect loading on the intervertebral joints. Imbalanced muscle activation can lead to inappropriate magnitudes of muscle force and stiffness, thereby loading the spine incorrectly and inducing low back pain and musculoskeletal injury.[9] Brown and McGill[40] stated that, under conditions of static equilibrium, the stiffness produced by a muscle will function in a stabilizing manner, while its force can function in either a stabilizing or destabilizing manner, depending on the orientation of the muscle about the joint. Considering that the relationship between force and stiffness is non-linear and a situation in which the orientation of a muscle is such that its instantaneous tension acts in a destabilizing manner about a joint, there may exist a critical force level at which any additional increase in force becomes dominant over the corresponding stiffness increase, thereby reducing the stabilizing potential of the muscle.[40] Comerford and Mottram[24] stated that there is a clear link between reduced proprioceptive input, disturbed slow motor unit recruitment and the development of chronic pain states. Deficient core neuromuscular control may predispose athletes to low back injuries as well as injuries of the lower extremity. With respect to low back problems, a delayed reflex response of trunk muscles is found to be a pre-existing risk factor for sustaining a low back injury in athletes.[10] Furthermore, because >90% of sports-related low back injuries occur from self-initiated actions such as jumping, running or cutting, it is likely that a deficit in motor control is a causative factor in these injuries.[32] This statement is supported by the findings of Gill and Callaghan,[34] who reported a significant decrease in repositioning ability in patients with low back pain. They concluded that precise muscle spindle input is a vital aspect for accurate positioning of the pelvis and lumbo-sacral spine.[34] In addition, subjects with low back pain have been shown to demonstrate impaired postural control, delayed muscle reflex responses following sudden trunk Sports Med 2008; 38 (11)

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unloading and abnormal trunk muscle recruitment patterns.[10] Furthermore, athletes with a history of low back pain continued to demonstrate motor control deficits of the trunk, even after clinical recovery and return to their prior level of competition.[10] With regard to knee injuries, Zazulak et al.[10] showed that decreased neuromuscular control of the body’s core, measured during sudden trunk unloading and trunk repositioning tasks, is associated with an increased risk of knee injury in athletes. Dynamic stability of an athlete’s knee is defined as the ability of the knee joint to maintain intended trajectory after internal or external disturbance.[10] It depends on accurate sensory input and appropriate motor responses to deal with rapid changes in trunk position during manoeuvres such as cutting, stopping and landing. Deficits in neuromuscular control of the body’s core may compromise dynamic stability of the lower extremity, resulting in increased abduction torque at the knee.[10] As a result of this, strain on the knee ligaments is increased, leading to injury. In the study by Zazulak et al.,[10] the strongest predictor of injury in the female athletes was found to be the magnitude of displacement, in particular laterally, during sudden trunk unloading. In addition, active proprioceptive repositioning error and history of low back pain were also related to a higher risk of sustaining a knee injury.[10] Zazulak et al.[4] reported deficits in active proprioceptive repositioning in women with knee injuries and ligamental or meniscal injuries, compared with uninjured women. These deficits are measured prospectively, indicating that they may predispose female athletes to knee injury. In contrast, no differences in proprioceptive repositioning error were found between injured and uninjured men.[4] Thus, in female athletes, impaired core proprioception may lead to impaired control of the core, which in turn negatively affects control of the knee and consequently may lead to knee injury.[4] With respect to male athletes, Zazulak et al.[10] found that the core proprioception deficits were only significant knee injury predictors for the ligament-injured group. In this group, ª 2008 Adis Data Information BV. All rights reserved.

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history of low back pain was shown to be the strongest predictor of knee injury.[10] 3. Core Stability, Neuromuscular Core Control and Balance In section 2, we have seen that dysfunction of spinal structures, dysfunction of trunk muscles or neuromuscular deficits can result in spinal instability. Instability of the spine is an important aspect of low back pain, since it can lead to excessive tissue strain and consequent pain.[14] Comerford and Mottram[24] stated that the muscles in the local system do not demonstrate consistent strength deficits or changes in length. The importance of the neural control over the trunk muscles was underlined by Barr et al.,[39] who noted that back pain has been found to be associated with deficits in spinal proprioception, balance and with deficits in the ability to react to unexpected trunk perturbation. We have also seen before that deficits in neuromuscular control of the body’s core may lead to uncontrolled trunk displacement during athletic movement. This, in turn, may increase knee abduction motion and torque, place the lower extremity in a valgus position and result in increased strain on the knee ligaments and in anterior cruciate ligament injury.[10] Sections 3.1–3.4 discuss the relationship between impaired muscular core control, poor balance performance and spinal stability, by considering various results of EMG and balance studies, mainly conducted in patients with low back pain. 3.1 Delayed Muscle Reflex Response in Patients with Low Back Pain

Deficiencies in motor control of the lumbar spine have been proposed as one of the factors predisposing a person to experience a low back injury. This is supported by findings that patients with low back pain, who were being exposed to sudden trunk loading, exhibited longer trunk muscle response latencies than healthy controls.[41] In addition, Ebenbichler et al.[12] noted that the timing of feed-forward contractions of the abdominal muscles in preparation of an arm movement task seems to be disturbed in these Sports Med 2008; 38 (11)

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patients. Whereas healthy subjects tend to contract the transversus abdominis before other muscles to stabilize the spine in anticipation of limb movement, patients with low back pain show a delayed contraction of this muscle.[36] Radebold et al.[42] and Cholewicki et al.[32] measured reflex responses from 12 major trunk muscles during sudden force release experiments in subjects with chronic low back pain and in athletes with a history of an acute low back injury. These responses were short-latency reflexes most likely associated with muscle spindle activity. It was shown that subjects with low back pain had significantly longer latencies, both in the offset of agonistic and in the onset of antagonistic muscles.[32,42] These longer latencies were seen in response to sudden force release in flexion, extension and lateral bending directions. In comparison with healthy controls, the individual muscle reaction times of the patients showed greater variability.[42] In addition, Cholewicki et al.[32] also found that athletes with a recent history of an acute low back injury shut off significantly fewer muscles. This was supported by the findings of Cholewicki et al.[41] that athletes with low back injuries shut off a significantly smaller number of muscles in trunk flexion. Furthermore, athletes with a history of low back injury switched on a smaller number of trunk extension muscles than athletes without such a history. The results of Cholewicki et al.[41] also showed that delayed switch-off latencies of the abdominal muscles in flexion and lateral bending are a significant predictor of a future low back injury in athletes. All these results enhance our understanding of the mechanisms underlying low back injuries. They are in favour of the hypothesis that a delayed muscle reflex response increases the vulnerability of the spine to injury under sudden loading conditions. An alternative to the hypothesis of delayed muscle reflex response as a risk factor is the hypothesis that the delayed response is caused by the injury or pain itself. Damage to the receptors within the soft tissues of the lumbar spine could impair the feedback control and in turn delay the reflex response.[41] Another alternative is the hypothesis that the delayed muscle reflex is a ª 2008 Adis Data Information BV. All rights reserved.

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compensation mechanism, adopted by the patient with low back pain to compensate for an injured and unstable spine or to avoid pain. However, Cholewicki et al.[41] found no significant change in muscle reflex latencies following a low back injury among athletes who reported no history of injury, indicating that delayed muscle response to sudden trunk loading is a significant predictor of a future low back injury. 3.2 Neuromuscular Imbalance in Patients with Low Back Pain

An adequate response to sudden loading depends also on correct muscle recruitment patterns to assure the mechanical stability of the lumbar spine.[42] Besides altered timing, motor control deficits also present as altered patterns of recruitment. Comerford and Mottram[24] stated that there is evidence of alteration of normal recruitment, both in peripheral and in local trunk stability muscles, which is associated with pain or pathology. These alterations are present under normal functional movement conditions. The only consistent evidence of failure of the muscles in the local system is in the regulation of muscle tension to control segmental motion and to recruit prior to loading of the joint system, thereby enhancing stability during function.[24] The end result of this altered recruitment pattern is a loss of functional or dynamic stability. Renkawitz et al.[33] found distinct neuromuscular imbalances between right and left erector spinae at the lumbar level during maximum voluntary trunk extension among athletes with low back pain, whereas there were no significant EMG-activity imbalances in subjects without low back pain. These results support the hypothesis that neuromuscular imbalance is associated with low back pain, especially in athletes participating in sports with high demands on the back. However, Renkawitz et al.[33] also stated that not every neuromuscular imbalance is a pathological finding. For achieving top athletic performance, unilateral neuronal and muscular adjustments are sometimes important preconditions. Van Diee¨n et al.[13] conducted a study in which trunk muscle recruitment patterns in patients with Sports Med 2008; 38 (11)

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chronic low back pain were compared with those in healthy control subjects. They found that the ratios of antagonist over agonist and the ratios of lumbar over thoracic erector spinae EMG amplitude were greater in the patients than in the control subjects.[13] In addition, Radebold et al.[42] demonstrated a significantly different muscle recruitment pattern in response to sudden load release between patients with chronic low back pain and healthy control subjects. The patients maintained agonistic muscle contraction while their antagonistic muscles became concurrently activated, whereas the electromyograms of healthy control subjects showed a switch from agonistic to antagonistic muscle contraction, not exhibiting co-contraction in muscle recruitment patterns. Furthermore, patients showed large variability in the recruitment pattern of individual muscles compared with the healthy control group.[42] Without a prospective study it is hard to answer the question whether neuromuscular imbalances are a result or a cause of low back pain. In their study, Radebold et al.[42] considered the differences exhibited within the chronic low back pain group to represent specific muscle response patterns, necessary as a compensation mechanism to stabilize their lumbar spine in response to sudden loading. In addition, Van Diee¨n et al.[13] suggested that the changes in muscle activity in patients with low back pain should be regarded as functional adaptations in response to a reduced spinal stability. But even if the muscle co-activation pattern after sudden loading is an adaptation mechanism, it also is an indicator of abnormal function for which the individuals need to compensate.[32] 3.3 Balance Performance in Relation to Core Stability

Now that the relationship between neuromuscular control and core stability has been discussed, let us now consider what is known about balance performance in relation to core stability and neuromuscular core control. Maintenance of balance in upright posture is essential in practicing daily activities and sports, also with respect ª 2008 Adis Data Information BV. All rights reserved.

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to the prevention of injury. Stabilization of the trunk is crucial for maintaining static or dynamic balance, especially to provide a solid base when attempting to exert forces upon external objects.[21] However, there is little research documenting the effects of balance on performance measures such as, for example, force and power. Within the human body there are a number of neuromuscular mechanisms that are responsible for the maintenance of balance. Balance is achieved through an interaction between central anticipatory and reflexive actions and these actions are assisted by the active and passive restraints caused by the muscular system.[21] There exist continuous afferent and efferent control strategies within the sensory motor system, using feedback from somatosensory, vestibular and visual inputs, with the vestibular system being considered as the main controller.[21] Standing on an unstable support calls upon higher levels of the control system and requires an essential change in the mode of utilization of incoming proprioceptive information. Kornecki et al.[43] reported that, when standing on an unstable support, the myopotentials of the stabilizing muscles precede the instant of force application. Slijper and Latash[44] reported such an anticipatory increase in activity of, among other muscles, the erector spinae and the rectus abdominis. These anticipatory postural adjustments minimize the subsequent postural destabilization. Two mechanisms are proposed to underlie the negative effect of postural instability on balance, namely an alteration of proprioceptive messages at the peripheral level and alterations in central processing.[21] Spinal proprioception and balance have been found to be abnormal in patients with chronic low back pain.[45,46] In addition, postural stability and one-foot balance have been found to be significantly reduced in these patients, suggesting that they posses poor central and peripheral balance control mechanisms.[12] 3.4 Relationship between Balance Performance and Neuromuscular Core Control

Only one study[26] has been found examining the relationship between balance performance Sports Med 2008; 38 (11)

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and trunk muscle properties. In this study, it was investigated whether trunk muscle response to quick force release was correlated with balance performance in unstable sitting. It was shown that patients with chronic low back pain have poorer postural control of the lumbar spine than healthy control subjects and this difference increased with increasing task level. Most importantly, in the absence of visual feedback, poor balance performance correlated significantly with longer trunk muscle onset times in response to sudden force release. The authors noted that this finding suggests the existence of a common pathology underlying both phenomena.[26] In this study by Radebold et al.,[26] two different motor control pathways were addressed, namely the spinal reflex and the brain stem pathway. These pathways are both dependent on proprioception and other sensory inputs, on central information processing and on appropriate motor output. It is quite likely that poor postural control and delayed muscle response are due to a deficit in one or more of these components.[26] The significant correlation between the average muscle onset time and balance performance was only found in the eyes closed condition. The more pronounced deficiency in postural control during this condition was suggested to exist because of the remaining sensory input systems being more challenged in the absence of visual feedback.[26] It is also interesting to note that the healthy control subjects controlled their posture better in the sagittal plane than in the lateral direction, although the patients with low back pain showed no difference between the two directions.[26] It was suggested that fine postural adjustments might be easier in the sagittal plane, because all joints have a much greater range of motion or even move exclusively in that direction. However, in the case of a disturbed proprioception, as in patients with low back pain, those subtle differences may disappear. Therefore, balance performance, measured in the anterior/posterior direction, might best discriminate between patients with low back pain and healthy control subjects.[26] ª 2008 Adis Data Information BV. All rights reserved.

4. Training Core Stability Strength and endurance of the trunk musculature and torso balance are said to be important for core stability, appropriate posture and maximal performance during sports.[47] To enhance athletic performance and to prevent or rehabilitate various lumbar spine and musculoskeletal disorders, strengthening or facilitation of the core muscles has been advocated.[2] There is a need to develop exercise programmes and therapeutic strategies based on academic and clinical evidence. Although the use of core strengthening programmes is widespread, little research has been conducted on the efficacy of these programmes. The goal of core stability exercise programmes is enabling performance of high-level activities in daily life and sports, while keeping the spine stabilized.[39] In sections 4.1–4.3, some proposals are highlighted about what aspects of the core should be trained and how to train them. Subsequently, the importance of proprioceptive training will be discussed with special attention towards the role of Swiss ball training in improving core stability.

4.1 Functional Training of Both the Local and Global Muscle System

Rehabilitation strategies include specific mobilization of articular and connective tissue restrictions to regain myofascial extensibility.[19] Retraining of the global stability muscles is required to control myofascial compensations and the local stability system should be trained for appropriate muscle recruitment to control segmental motion by increasing muscle stiffness.[19] Besides the deep and the global musculature, other components that can be improved by exercise include muscles that increase intra-abdominal pressure to increase lumbar stability and the precise neural control of the lumbar muscles so that they fire in a normal and efficient manner.[39] The focus of core stability training should be on the integration of local and global stabilizer muscles, which is important to control the neutral joint position.[19] Sports Med 2008; 38 (11)

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One of the greatest challenges in training the core is the integration of specific training regimens into functional activities. Isolation of specific muscles or joints should be avoided in core stabilization exercises and the emphasis should be on the training of muscle activation sequences in functional positions and motions.[3] This way, normal biomechanical motions are restored through normal physiological activations. The eventual goal is to make the required muscle recruitment automatic and to achieve an adequate coordination of activation of the segments that are part of the kinetic chain.[3] 4.2 Core Strengthening: Coordinative and Proprioceptive Training

Anderson and Behm[21] noted that resistance training, besides its effect of increasing muscular strength, also increases the coordination of synergistic and antagonist muscle activation, thereby improving stability. It is known that strength gains can be due to both increases in the cross-sectional area of the muscles involved and due to improvements in neuromuscular coordination. The neural adaptations occurring in the early phase of a resistance training programme lead to an improved coordination of stabilizing muscles.[21] Comerford and Mottram[19] stated that motor control and recruitment are the priority in stability retraining. In addition, Akuthota and Nadler[2] stated that motor relearning may be more important than strengthening in patients with low back pain. Emphasizing the improvement in neuromuscular function of the trunk muscles may have positive effects with respect to the prevention of repeated injuries to the lower back or in reducing recovery time.[32] Furthermore, Hewett et al.[48] suggested that neuromuscular core training would also improve dynamic stability of the knee joint. Zazulak et al.[4] stated that there is strong evidence for the use of neuromuscular training to improve neuromuscular control of the trunk and lower extremity. Research by Caraffa et al.[49] showed that neuromuscular control can be enhanced by joint stability exercises, balance training, perturbation training, plyometric or jump exercises and ª 2008 Adis Data Information BV. All rights reserved.

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sport-specific skill training. Perturbation programmes challenge the propriocepsis, for example by using wobble boards, roller boards, discs and Swiss balls. The sensitivity of afferent feedback pathways is increased through balance and motor skill training. By improving the sensitivity of the position sense of muscle and joint receptors, the onset times of stabilizing muscles is improved.[21] Wilder et al.[50] showed that, after a rehabilitation lasting only 2 weeks in which the back extensors were actively trained, muscle reaction times in patients with chronic low back pain decreased significantly down to a level similar to that of healthy volunteers. In addition, Hides et al.[51] found that patients with acute low back pain who received training in co-contracting the multifidi and transversus abdominis muscles had much less chance of recurrence of low back pain than a control group who did not receive this training. Renkawitz et al.[33] found that both the number of tennis players with low back pain and the occurrence of neuromuscular imbalance in the lumbar region decreased significantly as a result of dynamic neuromuscular changes after a sport-specific home exercise programme lasting 7 weeks. Based on these findings, it may be helpful to evaluate athletes for proprioceptive deficits before competition and to target them for specific active neuromuscular training when needed. 4.3 Swiss-Ball Training

Training on labile surfaces will challenge the musculature and by training the body to handle unexpected perturbations, balance and proprioception may improve.[2] Unstable training environments stress the stabilizing role of the musculature at the expense of functional force production. The goal of such training methods is to accommodate to an unstable environment, thereby diminishing the loss of force.[21] Numerous training aids have been developed to create a training environment in which functional performance can be enhanced, one of them being the so-called Swiss ball. Several studies have been conducted on the effectiveness of Swiss-ball training with respect to the improvement of Sports Med 2008; 38 (11)

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core stability. Marshall and Murphy[52] found increased activity of the rectus abdominis, transversus abdominis and the internal obliques while performing different core stability exercises (single-leg hold and press-up) on a Swiss ball, compared with exercising on a stable surface. In addition, Behm et al.[53] showed an increase in the activation of the deep abdominal stabilizers as well as the lumbo-sacral and upper lumbar erector spinae during trunk strengthening exercises on a Swiss ball. Besides the increase in EMG activity, Cosio-Lima et al.[47] also demonstrated an improved performance on a static balance task after a 5-week functional training programme with a Swiss ball compared with conventional floor exercises in untrained women. Stanton et al.[27] assessed certain strength and endurance aspects of the core as measured by the Sahrmann test (see section 5 for further description) and it appeared that 6 weeks of Swiss-ball training significantly improved performance on the test. From these findings, it can be concluded that the use of unstable surfaces such as a Swiss ball stresses the propriocepsis and increases the extent of activation of the trunk muscles that are important for balance and stability in sport.

5. Measuring Core Stability This section looks at the various ways in which core stability has been assessed in the past few years. Usually doctors and therapists manually perform clinical testing of segmental spine stability,[12] but to date no objective quantitative measurements are available for clinical use. In section 1 of this article, we have seen that some authors stress the importance of muscular strength in providing core stability. Kibler et al.[3] stated that no standard way has been described to measure core strength. Section 5.1 discusses some issues related to the measurement of core strength and endurance and subsequently, various methods will be presented in which neuromuscular control and coordination of the muscles around the lumbar spine have been assessed in the past few years. ª 2008 Adis Data Information BV. All rights reserved.

5.1 Measuring Core Strength and Endurance

Several investigators have used different techniques in trying to determine the relative strengths of specific core muscles via isometric dynamometer values and EMG data.[3] These data can give an estimate of core strength. Evaluation of any specific single muscle as a reference point is questionable because, to provide core strength, numerous muscles fire in task-specific patterns. In their review, Kibler et al.[3] proposed to assess core strength by qualitatively looking at one-leg standing balance ability and a one-leg squat and by conducting a standing, three-plane core strength test. Three-plane core testing is an attempt to quantify control of the core in the different planes of spine motion.[3] Patients stand, either on one leg or on both legs, a given distance away from a wall. Starting from different initial positions, they have to slowly move their body toward the wall, without hitting it. Reduced ability to maintain single-leg stance and reduced ability to just barely touch the wall are associated with decreased core strength.[3] Although clinical experience has demonstrated that this battery of tests gives useful information, allowing the design of specific rehabilitation protocols for increased core function, no specific studies have been conducted to determine reliability and validity of the three-plane core strength test.[3] Therapy should focus on the muscles working in the planes of motion that are found to be deficient.[3] The observation of posture is of additional value with respect to specific flexibility and strength testing. Patients should be evaluated for common muscle imbalances that affect the ability to maintain a neutral spine position.[39] For this purpose, the use of ultrasound or fine-needle EMG may become of great value, although it has to be noted that this measurement method is very impractical to use in a clinical setting. There is no consensus about the question whether strength testing of the abdominals and spine extensors is clinically valuable. One reason for this variability in the literature may be the different strength requirements that patients have.[39] With respect to the measurement of trunk muscle endurance, Stanton et al.[27] conducted a Sports Med 2008; 38 (11)

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study in which subjects were required to adopt a push-up position with the elbows locked and the toes placed on the vertical apex of a Swiss ball, so that the subject was parallel to the ground. When the hip flexion angle reached a deviation of >101 from the angle determined at the start of the test, the time of failure was recorded. In addition, a clinical measure of the strength and endurance capacity of the core was obtained using the Sahrmann core stability test.[27] During this test, while the subject is lying supine, an inflatable pad of a Stabilizer Pressure Biofeedback Unit is placed in the natural lordotic curve and is inflated to 40 mmHg. The test consists of five levels in which the subject has to make certain leg movements, with each level increasing in difficulty. During each level, the pressure on the Biofeedback Unit is noted and a deviation of >10 mmHg from a particular baseline value indicates that lumbo-pelvic stability is lost.[27] Kavcic et al.[54] conducted a study of which the purpose was to quantify tissue loading characteristics and lumbar spine stability resulting from the muscle activation patterns that were measured when selected stabilization exercises were performed. During the investigation, ten male subjects performed a series of eight different exercises, while external forces, 3-dimensional lumbar motion and electromyography were measured. In order to calculate a measure of L4–L5 compression and spine stability, the measured data were input into a series of biomechanical models. The value for stability (stability index) was obtained by calculating a level of potential energy in the lumbar spinal structure for each of the 18 degrees of freedom (three rotational axes at six lumbar joints). This stability index resulted from the combined potential energy existing in both the passive and active spinal structures, minus any work added by external loads. This way, 18 values of potential energy were obtained that were formed into an 18 ·18 Hessian matrix and diagonalized. The index of spine stability was represented by the determinant of this matrix. Based on this index, together with muscle activation levels and lumbar compression, Kavcic et al.[54] produced a rank order of the various stabilization exercises they had selected. ª 2008 Adis Data Information BV. All rights reserved.

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5.2 Measuring Neuromuscular Control and Coordination

As mentioned in section 1 of this article, sensory motor control of the tissues around the lumbar spine plays an important role in providing core stability. In their study, Marshall and Murphy[52] considered optimal stabilization to be increased muscle activation of the ventrolateral abdominals compared with the rectus abdominis activation. They calculated the ratio of the ventrolateral abdominal and erector spinae muscle activity expressed relative to the rectus abdominis, based on the percentage of maximum voluntary contraction, to determine the synergistic relationship between these muscles.[52] Liemohn et al.[1] conducted a study of which the major purpose was to develop a measurement schedule, enabling quantification of core stability. They noted that coordination and balance are key elements in core stability training activities and so they chose to measure core stability through balance tests in which actual core stability training postures were replicated.[1] For this purpose, a stability platform was used on which balance had to be maintained in three different postures, namely kneeling arm raise, quadruped arm raise and the bridging posture. The duration of the balance tasks was 30 seconds and the tilt limits of the balance board were set at 51 to either side. The number of seconds that the subject could not maintain balance within the range of the tilt limits was recorded.[1] Radebold et al.[26] also assessed core stability through a balance task, namely an unstable sitting test. Subjects were placed on a seat equipped with a foot support, thereby preventing movement of the lower extremities (figure 1). Polyester hemispheres of varying diameter were attached underneath the seat, providing four levels of seat instability. The seat was placed on a force plate at the edge of a table. Displacements of the centre of pressure underneath the seat were measured with the force plate, while the subjects performed trials with eyes open and closed. The sitting task was chosen to verify that deficits in the postural control mechanism could still be identified when the lumbar spine was studied in isolation from the Sports Med 2008; 38 (11)

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Trunk angle

EMG Magnet release

postural control of lower body joints. This test was designed to assess the brain stem postural control pathway.[26] The same authors[26] also used a test to assess the spinal reflex motor control pathway. During this test, subjects were placed in a semi-seated position in an apparatus that prevented motion of the lower extremities (figure 2). They exerted isometric trunk flexion, extension and lateral bending at a force level corresponding to 30% of maximal isometric trunk exertion. Subsequently, the resisted force was suddenly released with an electromagnet and the agonistic and antagonistic response time of 12 major trunk muscles (rectus abdominis, external and internal oblique, latissimus dorsi, thoracic and lumbar erector spinae)

Fig. 2. Trunk perturbation task. While the subject exerts isometric trunk flexion, extension or lateral bending, the resisted force is suddenly released by an electromagnet. Response times of 12 trunk muscles are measured using surface electromyography [EMG] (reproduced from Radebold et al.,[26] with permission).

Force plate CoP

Variable diameter hemisphere

Fig. 1. Sitting balance task. The subject is seated while arms and legs are fixed so that postural adjustments are only possible through trunk motion. The seat instability level is increased by decreasing the diameter of the hemisphere on the bottom of the seat. Displacements of the centre of pressure (CoP) underneath the hemisphere are measured using a force plate (reproduced from Radebold et al.,[26] with permission).

ª 2008 Adis Data Information BV. All rights reserved.

was measured using surface EMG.[26] Agonistic muscles were defined as muscles that are active before the force release and are expected to shut off after the release. Antagonistic muscles are inactive before the force release and are expected to respond with increased electrical activity after the release.[41] In addition to the EMG equipment, Zazulak et al.[10] used a Flock of Birds electromagnetic device to record trunk motion after the force release. The sensor was placed on the back at approximately the T5 level. Although the semi-seated position is not a functional athletic position, this posture was chosen to control for other potential neuromuscular response strategies by movement around the lower extremity joints.[26] In controlling the muscles around the lumbar spine, adequate core proprioception is of vital importance. Zazulak et al.[4] directly assessed core proprioception by measuring both active Sports Med 2008; 38 (11)

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and passive proprioceptive repositioning using an apparatus designed to quantify trunk proprioception. The apparatus produced passive motion of the lumbar spine in the transverse plane. Subjects were seated on this apparatus so that rotation took place around a vertical axis extending through the L4/L5 vertebrae. The seat was driven by a stepper motor at a steady, slow rate, thereby minimizing tactile cueing. The focus of the test was mainly on feedback from muscular and articular mechanoreceptors of the trunk.[4] Since the upper body remained fixed to the backrest with a seatbelt, the contribution of the vestibular system was eliminated. The lower body moved in the plane parallel to the ground. Subjects were initially rotated (21/sec) 201 away from the neutral spine posture and stayed in that position for 3 seconds. In the passive test, the subjects were slowly rotated (11/sec) back towards the original position by the motor. In the active test, the subjects rotated themselves after the clutch was disengaged from the motor drive. When the subjects perceived themselves to be in the original, neutral position, they stopped the apparatus by pressing a switch and subsequently the repositioning error was recorded.[4] In the active test, trunk muscles generate the movement and therefore muscle spindle feedback is involved. However, during the passive test, when muscles are not active, sensory feedback from muscle spindles is decreased.[4] Therefore, input from joint and cutaneous receptors likely plays a greater role in sensory feedback during passive repositioning. Hence, the level of input from the muscle spindles differed between the active and passive tests.[4] 6. Conclusions and Recommendations for Further Research The purpose of this article was to give an overview of the existing literature with respect to several issues associated with core stability. In defining the core, it was found that some authors include the hip musculature as being part of the core, while most authors only concentrate on the musculature surrounding the lumbar spine. For the facilitation of discussion about other issues ª 2008 Adis Data Information BV. All rights reserved.

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related to the core, it is proposed to leave the hip musculature out of consideration with respect to the concept of core stability, although the hip musculature is found to be very important in connecting the core to the lower extremities and in transferring forces from and to the core. In section 1 of this article, it was found that co-contraction of the trunk muscles, thereby creating stiffness which in turn creates sufficient stability, is very important in providing core stability. Besides stiffness, direction-specific muscle activations are also important in providing core stability, particularly when encountering sudden perturbations. The contributions of the various trunk muscles depend on the task being performed. Particularly for athletes, it is of great significance to find a precise balance between the amount of stability and mobility. It is also shown that, in the search for this balance, the role of sensory-motor control is much more important than the role of strength or endurance of the trunk muscles. Future research should further reveal the complex biomechanics and muscle activations, thereby allowing more detailed evaluation methods and more specific training or rehabilitation protocols. No positive relationship has been found in the literature between core stability and physical performance. More research in this area is needed with adequate training programmes and sufficiently sensitive measurement protocols. With respect to the association between core stability and injury, various studies have found that a decrease in core stability is related to a higher risk of sustaining a knee injury or low back pain. Furthermore, it is found that deficient neuromuscular core control predisposes athletes to low back and lower extremity injuries. In addition, studies conducted to correlate hip muscle characteristics with injury also found that decreased strength, poor endurance and delayed firing are associated with lower extremity and low back injuries. Based on these findings, it would be interesting for future research to look at the relationship between the activation speed of the trunk muscles and the speed of activation of the hip musculature. Furthermore, it is recommended to follow athletes through multiple Sports Med 2008; 38 (11)

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sport seasons, by making use of prospective longitudinal studies, to further investigate the relationship between core stability and injury risk. Several studies demonstrated that delayed firing of the trunk muscles and neuromuscular imbalance are associated with low back pain. In addition, decreased balance performance was also found to be related to the occurrence of low back pain. Only one study has been found in which the relationship between balance performance and trunk muscle response times is investigated. A significant correlation was found between poor balance performance in a sitting balance task and delayed firing of the trunk muscles during sudden perturbation and it was suggested that both phenomena were being caused by proprioceptive deficits. Further research is needed to lay a stronger foundation for this relationship. In addition, investigation is required to look for the cause of delayed muscle responses and to see whether decreased muscle response times actually result in a reduced risk of injury. With respect to the training of core stability, it is shown that stressing the propriocepsis during training activities leads to increased demands on trunk muscles, thereby improving core stability and balance, which are important aspects in sport. In this respect, creating unstable surfaces, for example through the use of a Swiss ball, is a clever way to stress the trunk muscles. In addition, in various articles the importance of functional training is emphasized. Further investigation is warranted to validate the use of Swiss balls in physical training programmes and future research is required to develop specific, functional training protocols in various sport domains and in the field of rehabilitation. In section 5, several tests were discussed in which balance, trunk muscle activation characteristics and proprioception have been measured. One study even tried to quantify core stability by calculating an index of spine stability. On the basis of findings discussed in section 3, it can be stated that sitting balance performance and trunk muscle response times may be good indicators of core stability, although much more ª 2008 Adis Data Information BV. All rights reserved.

research in this domain is needed to further ground the various relationships. Simple quantitative test procedures have to be designed and evaluated that are of clinical use and that reflect the sensory-motor control aspects of the neuromuscular system surrounding the lumbar spine. Taking practical issues into consideration, it can be noticed that the use of EMG measurements to investigate trunk muscle reaction times is quite demanding and expensive. It would be interesting to quantify core stability using a balance task, for example by measuring centre of pressure-displacements or by making use of accelerometry. Future research is required to develop such a task and to adjust it to the specific demands of various target groups, such as patients or athletes. The development of sensitive measures can lead to the identification of neuromuscular risk factors that predispose athletes to low back and lower extremity injuries. On the basis of such evaluations, interventions can be developed to modify the risk factors, thereby decreasing the risk of injury. Acknowledgements No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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8. Bergmark A. Stability of the lumbar spine: a study in mechanical engineering. Acta Orthop Scand 1989; 230 Suppl.: 1-54 9. McGill SM. Low back stability: from formal description to issues for performance and rehabilitation. Exerc Sport Sci Rev 2001; 29 (1): 26-31 10. Zazulak BT, Hewett TE, Reeves NP, et al. Deficits in neuromuscular control of the trunk predict knee injury risk: a prospective biomechanical-epidemiologic Study. Am J Sports Med 2007; 35 (7): 1123-30 11. Cholewicki J, Simons AP, Radebold A. Effects of external trunk loads on lumbar spine stability. J Biomech 2000; 33 (11): 1377-85 12. Ebenbichler GR, Oddson LI, Kollmitzer J, et al. Sensorymotor control of the lower back: implications for rehabilitation. Med Sci Sports Exerc 2001; 33 (11): 1889-98 13. Van Diee¨n JH, Cholewicki J, Radebold A. Trunk muscle recruitment patterns in patients with low back pain enhance the stability of the lumbar spine. Spine 2003; 28 (8): 834-41 14. Arokoski J, Valta T, Airaksinen O, et al. Back and abdominal muscle function during stabilization exercises. Arch Phys Med Rehabil 2001; 82 (8): 1089-98 15. Hodges PW, Richardson CA. Contraction of the abdominal muscles associated with movement of the lower limb. Phys Ther 1997; 77 (2): 132-44 16. Kavcic N, Grenier S, McGill SM. Determining the stabilizing role of individual torso muscles during rehabilitation exercises. Spine 2004; 29 (11): 1254-65 17. Cholewicki J, McGill SM. Mechanical stability of the in vivo lumbar spine: implications for injury and chronic low back pain. Clin Biomech 1996; 11 (1): 1-15 18. Cholewicki J, VanVliet JJ 4th. Relative contribution of trunk muscles to the stability of the lumbar spine during isometric exertions. Clin Biomech 2002; 17 (2): 99-105 19. Comerford MJ, Mottram SL. Functional stability re-training: principles and strategies for managing mechanical dysfunction. Man Ther 2001; 6 (1): 3-14 20. Crisco JJ, Panjabi MM. The intersegmental and multisegmental muscles of the lumbar spine. A biomechanical model comparing lateral stabilizing potential. Spine 1991; 16 (7): 793-9 21. Anderson K, Behm DG. The impact of instability resistance training on balance and stability. Sports Med 2005; 35 (1): 43-53 22. Cresswell AG, Oddsson L, Thorstensson A. The influence of sudden perturbations on trunk muscle activity and intraabdominal pressure while standing. Exp Brain Res 1994; 98 (2): 336-41 23. McGill SM. Low back disorders: evidence-based prevention and rehabilitation. Champaign (IL): Human Kinetics, 2002 24. Comerford MJ, Mottram SL. Movement and stability dysfunction: contemporary developments. Man Ther 2001; 6 (1): 15-26 25. Gandevia SC, McCloskey DI, Burke D. Kinaesthetic signals and muscle contraction. Trends Neurosci 1992; 15 (2): 62-5 26. Radebold A, Cholewicki J, Polzhofer GK, et al. Impaired postural control of the lumbar spine is associated with delayed muscle response times in patients with chronic idiopathic low back pain. Spine 2001; 26 (7): 724-30

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27. Stanton R, Reaburn PR, Humphries B. The effect of shortterm Swiss ball training on core stability and running economy. J Strength Cond Res 2004; 18 (3): 522-8 28. Tse MA, McManus AM, Masters RSW. Development and validation of a core endurance intervention program: implications for performance in college-age rowers. J Strength Cond Res 2005; 19 (3): 547-52 29. Ireland ML. The female ACL: why is it more prone to injury? Orthop Clin North Am 2002; 33 (4): 637-51 30. Nadler SF, Wu KD, Galski T, et al. Low back pain in college athletes: a prospective study correlating lower extremity overuse or acquired ligamentous laxity with low back pain. Spine 1998; 23 (7): 828-33 31. Nadler SF, Malanga GA, Bartoli LA, et al. Hip muscle imbalance and low back pain in athletes: influence of core strengthening. Med Sci Sports Exerc 2002; 34 (1): 9-16 32. Cholewicki J, Greene HS, Polzhofer GK, et al. Neuromuscular function in athletes following recovery from a recent acute low back injury. J Orthop Sports Phys Ther 2002; 32 (11): 568-75 33. Renkawitz T, Boluki D, Grifka J. The association of low back pain, neuromuscular imbalance, and trunk extension strength in athletes. Spine J 2006; 6 (6): 673-83 34. Gill KP, Callaghan MJ. The measurement of proprioception in individuals with and without low back pain. Spine 1998; 23 (3): 371-7 35. McGill SM, Grenier S, Kavcic N, et al. Coordination of muscle activity to assure stability of the lumbar spine. J Electromyogr Kinesiol 2003; 13 (4): 353-9 36. Hodges PW, Richardson CA. Inefficient muscular stabilization of the lumbar spine associated with low back pain: a motor control evaluation of transversus abdominis. Spine 1996; 21 (22): 2640-50 37. Hides JA, Richardson CA, Jull GA. Multifidus muscle recovery is not automatic after resolution of acute, firstepisode low back pain. Spine 1996; 21 (23): 2763-9 38. Panjabi MM. The stabilizing system of the spine, part 2: neutral zone and instability hypothesis. J Spinal Disord 1992; 5 (4): 390-7 39. Barr KP, Griggs M, Cadby T. Lumbar stabilization: a review of core concepts and current literature, part 2. Am J Phys Med Rehabil 2007; 86 (1): 72-80 40. Brown SH, McGill SM. Muscle force-stiffness characteristics influence joint stability: a spine example. Clin Biomech 2005; 20 (9): 917-22 41. Cholewicki J, Silfies SP, Shah RA, et al. Delayed trunk muscle reflex responses increase the risk of low back injuries. Spine 2005; 30 (23): 2614-20 42. Radebold A, Cholewicki J, Panjabi MM, et al. Muscle response pattern to sudden trunk loading in healthy individuals and in patients with chronic low back pain. Spine 2000; 25 (8): 947-54 43. Kornecki S, Kebel A, Siemienski A. Muscular cooperation during joint stabilization, as reflected by EMG. Eur J Appl Physiol 2001; 85 (5): 453-61 44. Slijper H, Latash M. The effects of instability and additional hand support on anticipatory postural adjustments in leg, trunk, and arm muscles during standing. Exp Brain Res 2000; 135 (1): 81-93

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45. Mok NW, Brauer SG, Hodget PW. Hip strategy for balance control in quiet standing is reduced in people with low back pain. Spine 2004; 29 (6): E107-12 46. O’Sullivan PB, Burnett A, Floyd AN, et al. Lumbar repositioning deficit in a specific low back pain population. Spine 2003; 28 (10): 1074-9 47. Cosio-Lima LM, Reynolds KL, Winter C, et al. Effects of physioball and conventional floor exercises on early phase adaptations in back and abdominal core stability and balance in women. J Strength Cond Res 2003; 17 (4): 721-5 48. Hewett TE, Paterno MV, Myer GD. Strategies for enhancing proprioception and neuromuscular control of the knee. Clin Orthop Relat Res 2002; 402: 76-94 49. Caraffa A, Cerulli G, Projetti M, et al. Prevention of anterior cruciate ligament injuries in soccer: a prospective controlled study of proprioceptive training. Knee Surg Sports Traumatol Arthrosc 1996; 4 (1): 19-21 50. Wilder D, Aleksiev A, Magnusson M, et al. Muscular response to sudden load: a tool to evaluate fatigue and rehabilitation. Spine 1996; 21 (22): 2628-39

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51. Hides JA, Jull GA, Richardson CA. Long-term effects of specific stabilizing exercises for first-episode low back pain. Spine 2001; 26 (11): E243-8 52. Marshall PW, Murphy BA. Core stability exercises on and off a Swiss ball. Arch Phys Med Rehabil 2005; 86 (2): 242-9 53. Behm DG, Leonard A, Young W, et al. Trunk muscle EMG activity with unstable and unilateral exercises. J Strength Cond Res 2003; 19 (1): 193-201 54. Kavcic N, Grenier S, McGill SM. Quantifying tissue loads and spine stability while performing commonly prescribed low back stabilization exercises. Spine 2004; 29 (20): 2319-29

Correspondence: Dr Koen A.P.M. Lemmink, Center for Human Movement Sciences, University Medical Center Groningen, University of Groningen, Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands. E-mail: [email protected]

Sports Med 2008; 38 (11)

Sports Med 2008; 38 (11): 917-930 0112-1642/08/0011-0917/$48.00/0

REVIEW ARTICLE

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Rheumatic Diseases Presenting as Sports-Related Injuries Fabio Jennings,1 Elaine Lambert2 and Michael Fredericson1 1 Division of Physical Medicine and Rehabilitation, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California, USA 2 Rheumatology Service of Sports, Orthopedics, and Rehabilitation Associates, Redwood City, California, USA

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Low Back Pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Neck Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Hip and Groin Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Peripheral Arthropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Autoimmune Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Crystal-Induced Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Lyme Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Pigmented Villonodular Synovitis (PVNS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Soft Tissue Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Bursitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Tendinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Enthesitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Carpal Tunnel Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Practical Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

917 918 920 920 922 923 924 925 926 926 926 927 927 927 928 929

Most individuals seeking consultation at sports medicine clinics are young, healthy athletes with injuries related to a specific activity. However, these athletes may have other systemic pathologies, such as rheumatic diseases, that may initially mimic sports-related injuries. As rheumatic diseases often affect the musculoskeletal system, they may masquerade as traumatic or mechanical conditions. A systematic review of the literature found numerous case reports of athletes who presented with apparent mechanical low back pain, sciatica pain, hip pain, meniscal tear, ankle sprain, rotator cuff syndrome and stress fractures and who, on further investigation, were found to have manifestations of rheumatic diseases. Common systemic, inflammatory causes of these musculoskeletal complaints include ankylosing spondylitis (AS), gout, chondrocalcinosis, psoriatic enthesopathy and early rheumatoid arthritis (RA). Low back pain is often mechanical among athletes, but cases have been described where spondyloarthritis, especially AS, has been diagnosed. Neck pain, another common mechanical symptom in athletes, can be an atypical

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presentation of AS or early RA. Hip or groin pain is frequently related to injuries in the hip joint and its surrounding structures. However, differential diagnosis should be made with AS, RA, gout, psudeogout, and less often with haemochromatosis and synovial chondochromatosis. In athletes presenting with peripheral arthropathy, it is mandatory to investigate autoimmune arthritis (AS, RA, juvenile idiopathic arthritis and systemic lupus erythematosus), crystal-induced arthritis, Lyme disease and pigmented villonodular synovitis. Musculoskeletal soft tissue disorders (bursitis, tendinopathies, enthesitis and carpal tunnel syndrome) are a frequent cause of pain and disability in both competitive and recreational athletes, and are related to acute injuries or overuse. However, these disorders may occasionally be a manifestation of RA, spondyloarthritis, gout and pseudogout. Effective management of athletes presenting with musculoskeletal complaints requires a structured history, physical examination, and definitive diagnosis to distinguish soft tissue problems from joint problems and an inflammatory syndrome from a non-inflammatory syndrome. Clues to a systemic inflammatory aetiology may include constitutional symptoms, morning stiffness, elevated acute-phase reactants and progressive symptoms despite modification of physical activity. The mechanism of injury or lack thereof is also a clue to any underlying disease. In these circumstances, more complete workup is reasonable, including radiographs, magnetic resonance imaging and laboratory testing for autoantibodies.

In daily practice, sports medicine practitioners see a variety of sports-related injuries. There is a temptation to attribute a mechanical diagnosis to every patient who presents with a joint complaint. However, it is necessary to maintain an index of suspicion for inflammatory joint diseases, especially rheumatic diseases. This article presents a literature review of rheumatic diseases presenting as sports-related injuries in five common conditions: low back pain, neck pain, hip/groin pain, peripheral arthropathy and soft-tissue disorders. Literature searches were based on the following key words: ‘athletes’, ‘rheumatic diseases’, ‘arthritis’, ‘low back pain’, ‘neck pain’, ‘ankylosing spondylitis’, ‘rheumatoid arthritis’, ‘reactive arthritis’, ‘systemic lupus erythematosus’, ‘gout’, ‘pseudogout’, ‘chondrocalcinosis’, ‘tendinopathies’, ‘bursitis’, ‘enthesitis’, ‘fibromyalgia’, ‘polymyositis/dermatomyositis’, ‘pigmented villonodular synovitis’ and ‘vasculitis’. Searches of citations in English from 1950 to 2007 (journal articles via PubMed and textbooks by the Lane Online Information System) were performed and all studies reporting rheumatic disorders in ª 2008 Adis Data Information BV. All rights reserved.

athletes were examined. Studies describing rheumatic diseases presenting as sports-related injuries were focused on. 1. Low Back Pain Low back pain is a common presenting complaint for the general population. Reported lifetime prevalence varies from 49% to 70% and point prevalences from 12% to 30% are reported in Western countries.[1] Low back pain is common in athletes, with its prevalence estimates ranging from 1% to >30%.[2,3] Low back pain is one of the most common reasons for missed playing time in professional athletes, yet the prevalence among recreational athletes is not well known. In the athletic population, the majority of low back pain is mechanical and is thought to be related to muscle strain or sprains of the ligamentous structures of the lower back. Disc herniation, compression fracture, spinal stenosis, and degenerative disease can occur in the mature athlete. In young athletes, the most common diagnosis is spondylolysis.[4] Sports Med 2008; 38 (11)

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It is interesting to note that disorders simulating athletic injury, including tumours and inflammatory connective tissue disease, may be encountered.[5] It has been estimated that about 5% of patients with chronic low back pain seen in the primary care setting are classified as having spondyloarthritis.[6] Another study in the US found that of all patients with back pain in primary care clinics, 0.3% have a diagnosis of ankylosing spondylitis (AS).[1] AS is a chronic inflammatory disease that belongs to the group of diseases called spondyloarthritis. Besides AS, which is the most frequent, spondyloarthritis comprises reactive arthritis or Reiter’s syndrome, arthritis/spondylitis associated with inflammatory bowel disease (enteropathic arthritis), arthritis/spondylitis with psoriasis or psoriatic arthritis, and undifferentiated spondyloarthritis. The leading clinical symptoms for all subsets of spondyloarthritis are inflammatory back pain and/or asymmetrical arthritis, predominantly of the lower limbs.[6] The European Spondyloarthropathy Study Group published a study aimed at developing classification criteria for the entire group of spondyloarthritis, with the specific intention of including patients with undifferentiated spondyloarthritis. The following classification criteria for spondyloarthritis were proposed: inflammatory spinal pain or synovitis (asymmetric or predominantly in the lower limbs), together with at least one of the following: positive family history, psoriasis, inflammatory bowel disease, urethritis, acute diarrhoea, alternating buttock pain, enthesopathy, or sacroiliitis as determined from radiography of the pelvic region.[7] Inflammatory low back pain is the hallmark of AS and is defined as pain associated with significant stiffness (especially morning stiffness for >1 hour), present for at least 3 months’ duration that improves with exercise, but is not relieved by rest.[8] Axial manifestations are seen less frequently in the other diseases and occur in 40% of patients with reactive arthritis, 10% in those with inflammatory bowel disease, and only 5% in persons with psoriatic spondyloarthritis.[6] Evaluating the incidence of AS in athletes, Wordsworth and Mowat[9] performed a review of ª 2008 Adis Data Information BV. All rights reserved.

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100 patients with AS and found that 61% of them had participated in regular athletic activity in their youth. The authors found that 30 of 45 male AS patients who exercised regularly had to reduce their activity level at an average age of 23 years. In contrast, the 30 healthy controls in this study continued to engage in their sports to an average age of 29 years. The most frequent initial symptoms of the patients with AS were low back pain (41%) and sciatica-like pain (25%). Given these symptoms, a physician might easily initially mistake AS for a sport-related injury. It has become increasingly evident that in many patients with AS, it takes years from the onset of inflammatory low back pain until the appearance of radiographic sacroiliitis. This is especially true in women, who may never develop radiographic changes. For example, Dick Tayler, a winner of the 10 000-m race at the 1974 Commonwealth games, had been continually plagued by low back pain and Achilles tendon disorders. He was later diagnosed as having AS, the consequences of which forced him to stop running.[10] The absence of radiographic sacroiliitis in the early stage of disease does not necessarily indicate absence of inflammation in the sacroiliac joint or other parts of the axial skeleton. Recent application of magnetic resonance imaging (MRI) techniques have demonstrated (and confirmed) that ongoing active inflammation does in fact occur in the sacroiliac joint or the spine prior to its appearance on plain radiographs. In light of this, some authors have proposed new or revised criteria to allow the early diagnosis of AS, especially since more effective treatment options have become available. New or revised criteria may comprise all parameters relevant to axial spondyloarthritis including inflammatory back pain, heel pain (enthesitis defined as the inflammation of the enthuses, which are any point of attachment of skeletal muscles or ligaments to bone), peripheral arthritis, dactylitis, acute anterior uveitis, family history of spondyloarthritis, good response to NSAIDs, elevated acute-phase reactants, human leucocyte antigen B27 (HLA-B27), sacroiliitis Sports Med 2008; 38 (11)

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(demonstrated on radiograph), and relevant MRI findings.[11] Until recently, the options available to clinicians for treating AS have been limited, with patient education, physical therapy, and NSAIDs being the mainstay of effective therapy. The advent of tumour necrosis factor-a (TNFa) antagonists represents a breakthrough in treating AS. Etanercept, infliximab and adalimumab, the three TNFa antagonists currently approved for the treatment of AS, have been demonstrated as being rapid and consistently effective in reducing the axial and peripheral symptoms and improving patients’ ability to function and their quality of life.[12,13] The physician assisting young athletes with low back pain with inflammatory characteristics must take into consideration the differential diagnosis with spondyloarthritis, especially AS. A high index of suspicion, early diagnosis and prompt treatment are crucial for slowing disease progression and enabling the athlete to maintain the greatest physical function. 2. Neck Pain Although the most common causes of neck pain are mechanical, the differential diagnosis for neck pain in athletes may be quite extensive and difficult. One should consider atypical cases of early rheumatoid arthritis (RA) and AS that may present with neck pain as the main symptom and when the symptoms appear to be more inflammatory than typically seen with soft-tissue or degenerative disorders. The polyarthropathy of RA affects the joints of the spine, and particularly the upper cervical spine.[14] Several studies of patients with RA suggest that the cervical spine becomes involved early in the course of disease, often within the first 2 years following the diagnosis. However, rheumatoid involvement of the cervical spine is often asymptomatic.[15] Patients with obvious arthritis in the hands are at increased risk for symptomatic cervical spine abnormalities. When the disease is unquestionably established, cervical spine radiographic abnormalities may include atlantoaxial (C1–2) subluxation, superior migration of the odontoid, subaxial ª 2008 Adis Data Information BV. All rights reserved.

arthritis, and collapse of the lateral masses of C1 from erosion at the facet joints.[16] Patients with diagnosed RA are at increased risk of spinal cord injury while participating in collision sports because of the increased incidence of cervical instability. Cervical subluxation may be found in 15% of RA patients within 3 years of diagnosis; 17% of RA patients with radiographic abnormalities have neurological symptoms.[17] Thus, a high index of suspicion is important for RA diagnosis when athletes complain of inflammatory neck pain especially with peripheral joint involvement. As cited above, spondyloarthritis, especially AS, usually affects men and starts in the lumbar spine and sacroiliac joints and subsequently spreads up to the thoracic and cervical spine. However, the disease may present with neck pain as the first manifestation without lower back pain or tenderness of sacroiliac joints, especially in women. Clinically, AS may present as gradual neck pain, stiffness and deformity that can cause great difficulty in performing everyday tasks and lead to a predisposition to fracture, dislocation and atlantoaxial subluxation.[18] Because of the mass fusion process of AS and altered biomechanical state, these patients are at high risk for sustaining spinal fractures that frequently occur after minor trauma and occasionally after no apparent or identifiable trauma. They are common in the lower cervical spine and occur frequently through the intervertebral disc.[19,20] There have also been case reports of cervical fracture in patients with AS following chiropractic manipulation.[21] 3. Hip and Groin Pain Hip or groin pain seems to occur frequently in sports involving twisting and turning, such as football, soccer, ice hockey, or basketball as well as in sports such as running with repetitive impact.[22] Pain may originate from the hip joint and its surrounding structures, as is seen with a labral tear, osteochondral defect, hip-joint synovitis, stress fractures of the femoral neck, and trochanteric bursitis. It also may arise from the adductor muscles where chronic muscle strain or tendinopathy Sports Med 2008; 38 (11)

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occur. Injury to the pubic bones may result in a pubic ramus fracture or osteitis pubis and can be the cause of a patient’s symptoms. Likewise, the lower abdominal muscles may be implicated in iliopsoas strain, rectus abdominis tendonopathy, or sports hernia. The lower thoracic spine, lumbar spine, and sacroiliac joint may refer pain to the groin. However, less common causes of pain in this region, such as some rheumatic disorders, must be considered.[23] The rheumatic diseases that can present as arthritis of the hip are spondyloarthritis (especially AS), RA, gout and pseudogout. Lovell[23] reviewed the case notes of 189 athletes with chronic groin pain. Diagnoses were determined following a review of their history, clinical examination, local anaesthetic infiltration, radiological investigation, surgical exploration, and clinical progress. The most common pathology was incipient hernia (50%). Other common diagnoses were adductor lesions, osteitis pubis, pubic instability, iliopsoas injuries, spinal nerve compression (referred to groin), rectus abdominis tendonopathy, and stress fractures. Only one patient was diagnosed as having AS, as he presented with sacroiliitis on a bone scan and tested positive for the HLA-B27 antigen. An example of a difficult and rare diagnosis of the hip and groin pain was described by Doward and co-workers.[24] They reported a case of a 34-year-old Olympic-calibre cyclist who presented with a 1-year history of progressive left hip and groin pain. Her symptoms initially began when she was running, but progressed to the point where they occurred with walking, cycling and lying on the hip. Clinical examination revealed moderately decreased internal rotation, external rotation, forward flexion, and abduction of the left hip compared with the right; and subjective complaints of deep hip pain with internal or external rotation. A radiograph of the left hip revealed slight hip joint narrowing centrally. An MRI arthrogram revealed a small anterior labral tear and innumerable small intermediateintensity filling defects situated diffusely within the joint fluid thought to be consistent with extensive reactive synovitis in the left hip. Arthroscopic removal of loose bodies was performed ª 2008 Adis Data Information BV. All rights reserved.

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and operative evaluation revealed no real labral tear, but damage at the labral cartilaginous junction anteriorly, some damage to the femoral head, and hundreds of cartilaginous loose bodies within the joint. After histological examination, the diagnosis of synovial chondromatosis was made. Seventeen months after surgery, this patient was able to return to her previous athletic activities. The authors suggested that with the increased awareness of labral tears as a source of hip pain in athletes it is important for physicians to keep other causes of hip synovitis in mind. McCurdie and Perry[25] reported two cases of haemochromatosis in patients who presented with exercise-related joint pain especially in the hip/groin initially attributed to their running. The patients were a 51-year-old female recreational runner, and a 34-year-old male keen road runner. In addition to hip pain, both subjects progressed with pain and stiffness over the second and third metacarpophalangeal joints. The female runner had no symptoms or signs of chronic liver disease or endocrine disturbance. She did, however, have plain radiographs showing degenerative changes in her hands, with hooked osteophytes at second and third metacarpals and both subtalar and talonavicular joints, as well as minor degenerative changes in both hips. The male runner presented with mild hepatomegaly and persistently increased liver function tests, with early fibrosis and heavy iron staining (but no cirrhosis) on liver biopsy. Also, plain x-ray films showed degenerative changes of the hips. In both cases, ferritin concentration was >1000 mg/L. They had a diagnosis of haemochromatosis and were referred to treatment with venosection. Their joint pains and arthropathy continued despite treatment, and they had bilateral total hip replacement. The authors conclude that the diagnosis of haemochromatosis is easily overlooked in patients presenting with exercise-related joint pain if the symptoms are attributed solely to their exercise and sporting activities. Idiopathic haemochromatosis is an inherited disorder of iron metabolism in which excess iron absorption leads to tissue damage associated with characteristic arthropathy. As many as 64% of patients with haemochromatosis develop arthropathy that has been recognized as an early manifestation and predominant clinical factor Sports Med 2008; 38 (11)

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affecting the quality of life of these patients.[26] Phlebotomy, the metal depletion treatment of choice in haemochromatosis, markedly improves survival and prevents complications.[27]

4. Peripheral Arthropathy With rare exceptions, any joint disorder is capable of presenting initially as monoarthritis.

Nonetheless, it is almost always possible to identify patients who need prompt evaluation and treatment to prevent rapid disease progression such as those with suspected septic arthritis. The physician must first attempt to localize the anatomical site of the abnormality. Joint pain may be the result of abnormalities of the joint itself, adjacent bone, surrounding ligaments, tendons, bursae, or soft tissue.[28] The range of disorders causing monoarthritis is listed in table I.

Table I. Differential diagnosis of peripheral arthritis (reproduced from McCune and Golbus,[28] with permission. Copyright ª Elsevier 2005) Usually monarticular

Often polyarticular

Common Septic arthritis bacterial

Rheumatoid arthritis Osteoarthritis

tuberculosis

Psoriatic arthritis

fungal

Reactive arthritis

Lyme disease Crystal disease

Calcium pyrophosphate deposition disease Most juvenile rheumatoid arthritis and juvenile spondylitis

gout

Systemic lupus erythematosus

pseudogout

Erythema nodosum

Internal derangement

Acute hepatitis B/C

Ischaemic necrosis

Rubella

Haemarthrosis

Lyme disease (usually £4 joints)

Trauma or overuse

Parvovirus

Pauciarticular juvenile rheumatoid arthritis

Other crystal-induced arthropathies

Congenital hip dysplasia

Enteropathic arthritis

Osteochondritis dissecans

HIV

Haemoglobinopathies Loose body Paget’s disease involving joint Stress fracture Osteomyelitis Osteogenic sarcoma Metastatic tumour Synovial osteochondromatosis Rare Pigmented villonodular synovitis

Whipple’s disease

Familial Mediterranean fever

Chronic sarcoidosis

Intermittent hydrarthrosis

Still’s disease

Behc¸et’s disease

Pulmonary hypertrophic osteoarthropathy

Regional migratory osteoporosis

Chondrocalcinosis-like syndromes due to ochronosis,

Amyloidosis (associated with myeloma or renal failure)

haemochromatosis, Wilson’s disease Rheumatic fever Paraneoplastic syndromes Polymyalgia rheumatica

ª 2008 Adis Data Information BV. All rights reserved.

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Of utmost importance is evaluation for septic arthritis, which is uncommon in the normal joint, but the possibility should be considered in joints recently drained or in patients with arthritis, diabetes mellitus or impaired immune function.[29] Synovial biopsy may play a role in the diagnosis of chronic, unexplained monoarticular arthritis, especially tuberculous synovitis.[28] Once infection is ruled out, certain rheumatic conditions must always be considered. Common diseases such as RA, gout, and pseudogout, or rarer diseases such as pigmented villonodular synovitis (PVNS) and intermittent hydrarthrosis may present as an acute monoarthritis. The patient history and physical examination are essential in determining the diagnosis. Inflammatory arthritis is characterized by stiffness of the affected joint that is most noticeable in the morning (morning stiffness of >1 hour) or after a period of inactivity (gelling) and that improves with motion. Also, inflammatory arthritis may often be associated with constitutional symptoms, such as fever or malaise, and involvement of multiple joints.[28] Occasionally, patients may attend the sports medicine clinic with multiple joint pains (polyarthralgia) or multiple joint pains with synovitis (polyarthritis). In many of these conditions, the diagnosis is clinical. A key diagnostic feature is the onset and pattern of joint involvement along with the extra-articular manifestations. For example, RA typically affects the small joints symmetrically, while reactive arthritis has a propensity to asymmetric involvement of large joints of the lower limb.[29] In table I, we summarize the conditions that present as polyarthritis. 4.1 Autoimmune Arthritis

Autoimmune arthritis such as RA and AS have been described to present as a sports-related injury in athletes. Jari and Noble[30] reported five cases of patients presenting with meniscal tears that were subsequently found to have RA. All five patients were middle-aged men who presented with a history and physical signs suggestive of medial meniscal tearing. These signs included a sudden twisting episode, medial joint line tenderness, and ª 2008 Adis Data Information BV. All rights reserved.

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a positive McMurray’s sign. Because MRI scans showed effusion and synovial thickening in addition to the medial meniscal tear, full blood count, erythrocyte sedimentation rate, and rheumatoid factor (RF) were also performed. In all patients, the erythrocyte sedimentation rate was raised and the RF was positive. In the three patients who had undergone surgery prior to their RF results being known, the surgical outcome was poor and results of the synovial biopsies were positive for RA. In two patients, surgery was deferred. These patients were successfully treated by a rheumatologist, and surgery was unnecessary. The authors suggest a policy of medical therapy to reduce inflammation in patients clinically suspected or diagnosed with RA before arthroscopic surgery is undertaken. Juvenile idiopathic arthritis is another diagnosis that should considered in athletes under the age of 16 years. Juvenile idiopathic arthritis identifies subtypes such as systemic arthritis, oligoarthritis, polyarthritis (RF-positive or -negative), enthesitisrelated arthritis, psoriatic arthritis and undifferentiated arthritis. Of special interest is the subtype enthesitis-related arthritis, which mainly affects males over the age of 6 years and is characterized by the association of enthesitis and arthritis. This arthritis commonly affects the joints of the lower extremity, especially the hips. The most common sites of enthesitis are the calcaneal insertions of the Achilles tendon, plantar fascia, and tarsal area. In some cases, arthritis could progress to affect the sacroiliac and spinal joints, thus producing the clinical picture of AS.[31] Although AS is known and named for spinal involvement, it can initially involve a peripheral joint, especially the shoulders and hips. Hill and Lombardo[32] described a case of AS presenting as shoulder pain in a 22-year-old athlete. This patient denied significant back pain and had been treated earlier with anti-inflammatory agents for the diagnosis of tendonitis. However, upon further questioning, the patient described intermittent episodes of iritis affecting both eyes. Results of his laboratory analyses revealed an elevated erythrocyte sedimentation rate, negative reactions to a RF test and antinuclear antibodies, and a positive test for HLA-B27. A pelvic roentgenogram Sports Med 2008; 38 (11)

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revealed fused sacroiliac joints bilaterally and ischial periostitis with normal hip joints. Roentgenograms of his shoulder showed marked jointspace narrowing, osteoporosis, and joint erosions. Six months after treatment with indomethacin and exercises, the patient had improved range of motion in the shoulder, decreased pain, and he was playing racquet sports with minimal discomfort. Arthritis is one of the most common manifestations that patients with systemic lupus erythematosus (SLE) exhibit over time. SLE is most often associated with female gender. The symmetric polyarticular pattern is the most common presentation and typically there is no evidence of erosive disease despite a spectrum of inflammatory synovitis and soft tissue swelling around the joints. However, it is usually the associated fatigue that patients complain of as the most debilitating symptom.[33] Besides arthritis and fatigue, the physicians can confirm diagnosis based on the other systemic signs and symptoms of SLE such as malar or discoid rash, photosensitivity, serositis, haematological, neurological or renal disorders, and positive autoantibodies. 4.2 Crystal-Induced Arthritis

Another aetiology of peripheral arthritis in athletes is gout. Gout is a metabolic disorder characterized by deposition of uric acid crystals in connective tissues and articular cartilage. The onset of gout usually occurs between the ages of 30 and 50 years.[10] More than 90% of patients with primary gout are men, and the age of peak incidence in men is earlier than that of affected women, who rarely develop the disorder before menopause.[34] One case exists of a 33-year-old male marathon runner who was admitted to hospital with a 6-day history of fever, chills, malaise and pain in his right knee and ankle following a 10-mile (16-km) run. A similar episode 2 years earlier had occurred, but instead of knee and ankle, his elbow was affected and was treated with antibacterials. He attributed chronic musculoskeletal back and groin pain to running and often took ibuprofen, aspirin (acetylsalicylic acid), or inª 2008 Adis Data Information BV. All rights reserved.

domethacin for relief. His usual alcohol consumption was about six beers a day. Laboratory data revealed a uric acid level of 10.0 mg/dL (normal 3.4–7.0 mg/dL). The diagnosis was made after aspiration of the knee, which yielded 50 mL of fluid that contained negatively birefringent intracellular crystals. A systolic murmur was also evident on cardiac examination, and an echocardiogram was performed, which revealed mild aortic regurgitation at the site of a nodule on the right coronary leaflet. The authors suggested that this nodule was visceral tophi. The patient was treated with intravenous colchicine and oral indomethacin, and all of his symptoms went into remission. He was discharged on 10 days of oral colchicine followed by allopurinol (300 mg/day) continuously, and 8 months later he was running without difficulty.[35] Mair and colleagues[36] described a case of gout as a source of sesamoid pain in an 18-yearold male intercollegiate wrestler, although gout is extremely rare in teenagers and young adults.[37] This patient presented with insidious pain in the region of the right first metatarsophalangeal joint and first metatarsal head without a specific prior injury. Radiographs revealed the medial sesamoid to be partitioned with minimal irregularity at the separated margins. It was thought that the patient might have had a stress fracture of the medial sesamoid. He was fitted with a carbon fibre insole and later an extended steel shank, and he refrained from wrestling for 8 weeks. The patient’s symptoms resolved, but when he resumed wrestling, he gradually began experiencing more pain. The decision was made to proceed with surgical exploration, which revealed a chalky, white material in the fragments of medial sesamoid that were cystic. Birefringent needles consistent with monosodium urate crystals were identified in the curetted material. The final pathological report confirmed the diagnosis of gout of the medial sesamoid. Following surgery, the patient did well and was able to resume wrestling without pain 3 months later. His serum uric acid level was 7.8 mg/dL (normal 3.5–8.0 mg/dL) and in retrospect, it was noted that his father had longstanding gout of the first metatarsophalangeal joint. It is important to emphasize that Sports Med 2008; 38 (11)

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actual determinations of solubility of monosodium urate in human plasma (or serum) indicate that saturation occurs at concentrations of about 7 mg/dL.[37] Exercise may increase serum uric acid by three mechanisms: (i) adenosine released by exercising muscle may be metabolized by purine nucleoside phosphorylase and xanthine oxidizes to produce uric acid; (ii) intense exercise and thermal stress may decrease renal blood flow and clearance of uric acid; and (iii) dehydration decreases plasma volume and increases the concentration of uric acid. Adding the fact that some athletes drink alcohol and take low doses of aspirin for overuse injuries, they are at increased risk for gout.[35] Pseudogout is a condition associated with deposition of calcium pyrophosphate dehydrate (CPPD) crystals and characterized by joint effusions with marked neutrophilia and a form of secondary osteoarthritis (OA) with a pattern of joint involvement that differs from primary OA. ‘Chondrocalcinosis’ is the term used to define the asymptomatic radiographic finding of calcification of articular or fibrocartilage most frequently related to CPPD deposition.[38] The cause of chondrocalcinosis is unclear, but it has been associated with several medical and hereditary problems. It has been reported to be common in patients with haemochromatosis, primary hyperparathyroidism and gout.[39] In addition to familial cases, another cause of chondrocalcinosis in young adults is thought to be trauma. Trauma-induced chondrocalcinosis tends to be monoarticular, involving the traumatized joint with degenerative changes, and occurs in relatively young persons without any predisposing medical condition. Trauma-induced monoarticular chondrocalcinosis has been found in internal derangements of the knee, hypermobile joints, and after surgery.[39] Another case report describes a 20-year-old man with a history of left knee discomfort of several months’ duration while training for and participating in an 800-m run for intercollegiate varsity track. He could not recall an episode of significant trauma and had no history of effusion or locking. He denied any known medical ª 2008 Adis Data Information BV. All rights reserved.

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problems, medications, steroid use, or familial history of arthritis. Radiographs revealed what appeared to be a 2- to 3-mm round, calcified, loose body in the lateral compartment of the knee. The differential diagnosis at this time was an osteochondral fracture or osteochondritis dissecans. A knee arthroscopy was performed and revealed thick, white, semisolid material of toothpaste consistency from a cavity at the tibial plateau articular cartilage. This material was excised and under microscope examination was found to be CPPD crystals. Radiographs taken 3 weeks postoperatively revealed that calcification was absent. He remained asymptomatic at 10 months’ follow-up and resumed his normal schedule. The authors suggested that chondrocalcinosis must be included in the differential diagnosis of intra-articular calcified lesions in young athletes with knee pain.[39] 4.3 Lyme Disease

Sportsmen, backpackers, and outdoor athletes may acquire unusual infectious diseases in the fields and forests of the US. One of these conditions, Lyme disease, is a tick-borne multisystem disorder caused by the spirochete Borrelia burgdorferi. It characteristically initiates with a particular lesion on the skin known as erythema migrans, which may be followed by neurological, cardiac, or articular abnormalities. Inflammatory arthritis is the most recognized feature of persistent infection, and approximately 60% of untreated patients develop monoarticular or asymmetric oligoarticular arthritis primarily in the large joints, with objective physical findings of synovial thickening or joint effusion. The diagnosis of Lyme disease is a clinical one. The serological test should be used to confirm the clinical diagnosis.[40,41] Seldes and colleagues[41] have described a 20-year-old male university football player who presented with an atraumatic spontaneous haemarthrosis of the left knee. This patient denied recent infection, fever, chills, night sweats, history of bleeding abnormalities, or sexually transmitted diseases. Eight months before his clinic visit, the patient noticed a ‘red splotchy rash’, which was diagnosed as an allergic reaction by a Sports Med 2008; 38 (11)

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dermatologist. Laboratory examinations, radiographs, and MRIs were not helpful. The diagnosis of Lyme arthritis was made based on his clinical examination and an unequivocally positive serological testing. After the treatment, which consisted of intravenous ceftriaxone 1 g/day for 14 days, the patient was asymptomatic. 4.4 Pigmented Villonodular Synovitis (PVNS)

Another uncommon cause of monoarthritis is PVNS. This benign disorder results in an increased proliferation of synovium, causing villous or nodular changes of synovial-lined joints, bursae, and tendon sheaths. Most patients present with monoarticular swelling, haemarthrosis, and a gradual increase in pain. The knee is the most common location followed by the hip, ankle and shoulder. Radiographic evaluation of PVNS often depicts increased soft-tissue density and may show bony erosions. MRI reveals low-signal intensity on both T1- and T2-weighted images. Histological examination confirms the diagnosis of PVNS. Partial or complete synovectomies are considered the treatment of choice.[42,43] A 30-year-old sportsman presented with knee pain after several twisting episodes during a game of football. On examination, there was specific anteromedial joint line pain, and results of a McMurray’s test were positive. A diagnosis of a medial meniscal tear was made. Arthroscopy, however, revealed a large pedicular lesion originating from the insertion of the anterior horn of the medial meniscus. Mini-arthrotomy was performed, and the diagnosis of PVNS was made after histological examination.[42] Mitchell and colleagues[44] reported a case of an 18-year-old division III college football player with a previous history of chondromalacia patella, who sustained a twisting injury of the right knee 3 days before presentation. He had a negative Lachman’s test. As he had a moderate effusion, aspiration of the joint was performed and yielded serosanguineous fluid. The clinical diagnosis was chondromalacia patella with irritation. After 6 months he returned complaining of a 1-month history of swelling and tenderness in the peripatellar area and over the vastus medialis ª 2008 Adis Data Information BV. All rights reserved.

muscle. On physical examination, he had a moderate effusion and crepitus over the lateral aspect of the patella and a possible intra-articular mass in that region. The clinical diagnosis at that time include a possible loose body with chondromalacia patella and a possible medial meniscal tear. Besides chondromalacia patella, MRI showed diffuse synovitis with probable PVNS. Arthroscopy was performed with shaving chondroplasty of the patella, and subtotal synovectomy. Histological evaluation confirmed the diagnosis of PVNS. Saxena and Perez[43] published a review of ten athletic patients with PVNS about the ankle. Most of the patients were previously involved in lateral motion sports such as basketball, tennis, soccer, or aerobics. Two patients ran for exercise. Nine of ten patients had a history of ankle sprains, with pain laterally. Plain radiographs showed bony changes about the talus and adjacent bones in four of ten patients; MRI showed PVNS findings in all ten. PVNS was found in multiple sites about the ankle including three ankle joints and two subtalar joints. All patients had synovectomy and tenosynovectomy, and eight were able to return to sports participation 4–12 months after surgery. 5. Soft Tissue Disorders Musculoskeletal soft tissue injuries are a leading cause of pain and disability in both competitive and recreational athletes. Incidence estimates are as high as 50% in distance runners.[45] Many of these injuries are acute tears or strain or are provoked by chronic muscle-tendon overload or overuse and muscle fibre ‘microtrauma’. However, these disorders may occasionally be a manifestation of a systemic rheumatic disease. 5.1 Bursitis

Bursae are small fluid-filled sacs located between tendons, muscles and bones that serve to cushion and reduce friction. Bursitis is defined as inflammation of these superficial or deep bursal sacs. The most common sites of bursitis included the olecranon bursa over the elbow region, the Sports Med 2008; 38 (11)

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trochanteric bursa in the hip, and the overlooked anserine bursa over the medial aspect of the knee. The presenting symptom is pain. Obvious swelling is seldom present except in the most superficial areas such as the elbow or knee. Besides local irritation and infection, bursitis can be associated with gout. Olecranon bursitis is especially more common in patients with gout or RA. In these cases, aspiration can be useful to determine the aetiology of the disorder.[46] Septic bursitis should always be considered for patients who have diabetes or who use intravenous drugs as well as for anyone who is immunocompromised. Patients with infected bursae usually have exquisite tenderness, redness, and heat over the bursal site and may have an elevated body temperature.[46] 5.2 Tendinopathies

Tendinopathies are often related to increased age, muscle imbalance, and anatomic malalignment. The most common sites are the supraspinatus, finger flexors, patellar and Achilles tendons.[46] Some tendinopathies, particularly lateral epicondylitis, have been associated with certain sports and occupational activities, in keeping with a presumed mechanical aetiology. One study found an increased prevalence of RF in patients with repeating lateral epicondylitis and wrist tenosynovitis suggesting that there may be an underlying predisposition to generalized rheumatic disease in some cases.[47] The frequency of tendon involvement in patients with RA has been reported to be as high as 64%, although most studies report lower frequencies. The most frequent sites for rheumatoid tendonitis are the hand extensors and flexors.[48] This is typically seen in the setting of synovitis and/or deformity. The number and incidence of tendon injuries in general have increased substantially during the last few decades, and this increase has been dominated by problems with the Achilles tendon. Because most Achilles tendon injuries take place in sports and there has been a common upsurge in sporting activities, the number and incidence of the Achilles tendon overuse injuries and complete ª 2008 Adis Data Information BV. All rights reserved.

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ruptures have increased in industrialized countries. In general, Achilles tendon problems arise from two origins: (i) excessive loading-induced degeneration of the tendon; and (ii) the tendon becomes the site for a systemic disease (e.g. gout, pseudogout, spondyloarthropathies and RA).[48] Although there is no description of tendon rupture in athletes due to rheumatic disease, it is described that RA, gout, CPPD deposition and SLE can lead to tendon rupture in young individuals. Among all tendon ruptures in RA, the most frequently ruptured tendons are hand extensors; all the other locations are clearly less common.[48] In RA, tendon rupture may occur, possibly by the overproduction of matrix metalloproteinases.[49] Gout has been described as a cause of peroneus tendon rupture in the presence of tophaceous gouty infiltration.[50] Although rare, extensor tendon rupture at the wrist associated with CPPD deposition has been described.[51] SLE can cause nonerosive joint deformities, but rarely can lead to spontaneous tendon rupture.[52] 5.3 Enthesitis

Enthesitis is defined as any pathological condition involving the entheses. The entheses are any point of attachment of skeletal muscles or ligaments to bone, where recurring stress or inflammatory autoimmune disease can cause inflammation or occasionally fibrosis and calcification. Plantar fasciitis is considered an enthesitis, and it is a common diagnosis in athletes usually having a mechanical aetiology. Other common sites are the ischial tuberosities, greater trochanters, spinous processes, costochondral and manubriosternal junctions, and iliac crests.[8] Enthesitis is also one of the main diagnostic criteria of spondyloarthritis, especially AS. However, spondyloarthritis presents with other inflammatory features such as low back pain with stiffness, peripheral asymmetric arthritis and elevated acute-phase reactants.[8] 5.4 Carpal Tunnel Syndrome

Carpal tunnel syndrome (CTS) is the most commonly diagnosed compression neuropathy in Sports Med 2008; 38 (11)

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the upper extremity. It usually begins as an isolated phenomenon, but symptoms of CTS can accompany many systemic diseases, such as congestive heart failure, amyloidoisis associated with multiple myeloma, hypothyroidism and tuberculosis. More commonly, CTS is associated with conditions such as pregnancy, diabetes, obesity, and any inflammatory arthritis affecting the wrist such as RA and gout.[53] The classic constellation of symptoms consists of weakness or clumsiness of the hand; paraesthesias in the thumb, index, and long fingers; and nocturnal paraesthesias in the affected digits. Patients may often complain of forearm and elbow pain that is aggravated by activities, but is poorly localized and aching in nature. The diagnosis of CTS is usually clinical. Bilateral electrodiagnostic tests should be used to confirm the diagnosis, particularly in patients with significant motor loss, atrophy or constant sensory loss or in patients with atypical signs or symptoms.[53]

The most common activities associated with the syndrome are those that require constant wrist flexion or use of vibrating tools. The symptoms of other disorders such as cervical disc disease, thoracic outlet syndrome, and more proximal entrapment of the median nerve may be confused clinically with CTS and need to be ruled out.[46]

6. Practical Recommendations Effective management of athletes presenting with musculoskeletal complaints requires a structured history, physical examination, and definitive diagnosis that distinguish the soft tissue problem from a joint problem and an inflammatory syndrome from a noninflammatory syndrome. Clues to a systemic inflammatory aetiology may include constitutional symptoms, morning stiffness, elevated acute-phase reactants and progressive

Table II. Clinical features and laboratory tests recommended to investigate rheumatic diseases Rheumatic disease

Clinical features

Laboratory tests

Rheumatoid arthritis

Small hand (MCP, PIP) and foot symmetric synovitis Tenosynovitis Carpal tunnel syndrome

Rheumatoid factor, anti-CCP antibody Radiographic changes (erosions or bony decalcification) Elevated ESR and CRP

Ankylosing spondylitis

Inflammatory low back pain, morning stiffness of >1 h Large joint synovitis Enthesitis Family history of spondyloarthritis Acute anterior uveitis/iritis

Radiographic sacroiliitis Elevated ESR and CRP HLA-B27 MRI findings of sacroiliitis

Gout

Arthritis of the first MTP joint Lower limb joint synovitis Tophi History of excessive alcohol ingestion

High uric acid levels Radiographic changes: bony erosion with ‘overhanging edge’ Synovial fluid analysis on compensated polarized microscopy

Chondrocalcinosis (CPPD deposition)

Small hand (MCP, PIP) and foot synovitis Family history History of repetitive trauma

Radiographic changes: typical calcifications Synovial fluid analysis on compensated polarized microscopy Ferritin levels (associated with haemochromatosis)

Systemic lupus erythematosus

Nonerosive arthritis Systemic manifestations: malar rash, photosensitivity, oral ulcers, serositis, renal disorder, neurological disorder, haematological disorder

Complete blood count: haemolytic anaemia, leucopenia, thrombocytopenia Proteinuria Antinuclear antibody test Anti-DNA/anti-Sm Antiphospholipid antibodies

CCP = cyclic citrullinated peptide; CPPD = calcium pyrophosphate dehydrate; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; HLA = human leucocyte antigen; MCP = metacarpophalangeal; MRI = magnetic resonance imaging; MTP = metatarsophalangeal; PIP = proximal interphalangeal.

ª 2008 Adis Data Information BV. All rights reserved.

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symptoms despite modification of physical activity. Also, the lack of injury mechanism suggests an underlying disease. In these circumstances, more complete workup is reasonable including radiographs, MRI and laboratory testing for autoantibodies. Table II summarizes the main clinical features and laboratory tests in the most common rheumatic diseases. 7. Conclusion There are many case reports of rheumatic diseases masquerading as a sports medicine condition. In the athlete with complaints of swollen joints, low back pain with stiffness, systemic symptoms, and without a history of trauma, inflammatory causes should be considered. The astute sports medicine practitioner should maintain an index of suspicion for rheumatic diseases as adequate and prompt treatment can modify disease progression, allowing the athlete to continue with regular exercise programmes. Acknowledgements No sources of funding were used in the preparation of this review and the authors have no conflicts of interest directly relevant to its contents.

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9. Wordsworth BP, Mowat AG. A review of 100 patients with ankylosing spondylitis with particular reference to socio-economic effects. Br J Rheumatol 1986; 25 (2): 175-80 10. Smart GW, Taunton JE, Clement DB. Achilles tendon disorders in runners: a review. Med Sci Sports Exerc 1980; 12 (4): 231-43 11. Rudwaleit M, Khan MA, Sieper J. The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria? Arthritis Rheum 2005; 52 (4): 1000-8 12. Clegg DO. Treatment of ankylosing spondylitis. J Rheumatol Suppl 2006; 78: 24-31 13. Manadan AM, James N, Block JA. New therapeutic approaches for spondyloarthritis. Curr Opin Rheumatol 2007; 19 (3): 259-64 14. Choi D, Casey AT, Crockard HA. Neck problems in rheumatoid arthritis: changing disease patterns, surgical treatments and patients’ expectations. Rheumatology (Oxf) 2006; 45 (10): 1183-4 15. Kim DH, Hilibrand AS. Rheumatoid arthritis in the cervical spine. J Am Acad Orthop Surg 2005; 13 (7): 463-74 16. O’Dell JR. Rheumatoid arthritis: the clinical picture. In: Koopman WJ, editor. Arthritis and allied conditions. Vol. 1. Philadelphia (PA): Lippincott Williams & Wilkins, 2001: 1153-86 17. Dorshimer GW, Kelly M. Cervical pain in the athlete: common conditions and treatment. Prim Care 2005; 32 (1): 231-43 18. Chou LW, Lo SF, Kao MJ, et al. Ankylosing spondylitis manifested by spontaneous anterior atlantoaxial subluxation. Am J Phys Med Rehabil 2002; 81 (12): 952-5 19. Shen FH, Samartzis D. Cervical spine fracture in the ankylosing spondylitis patient. J Am Coll Surg 2005; 200 (4): 632-3 20. Smith MD, Scott JM, Murali R, et al. Minor neck trauma in chronic ankylosing spondylitis: a potentially fatal combination. J Clin Rheumatol 2007; 13 (2): 81-4 21. Rinsky LA, Reynolds GG, Jameson RM, et al. A cervical spinal cord injury following chiropractic manipulation. Paraplegia 1976; 13 (4): 223-7 22. Bradshaw C. Hip and groin pain. In: Brukner P, Khan K, editors. Clinical sports medicine. 2nd ed. Sydney (NSW): McGraw-Hill; 2001: 375-94 23. Lovell G. The diagnosis of chronic groin pain in athletes: a review of 189 cases. Aust J Sci Med Sport 1995; 27 (3): 76-9 24. Doward DA, Troxell ML, Fredericson M. Synovial chondromatosis in an elite cyclist: a case report. Arch Phys Med Rehabil 2006; 87 (6): 860-5 25. McCurdie I, Perry JD. Haemochromatosis and exercise related joint pains. BMJ 1999; 318 (7181): 449-51 26. Adams PC, Speechley M. The effect of arthritis on the quality of life in hereditary hemochromatosis. J Rheumatol 1996; 23 (4): 707-10 27. Aaseth J, Flaten TP, Andersen O. Hereditary iron and copper deposition: diagnostics, pathogenesis and therapeutics. Scand J Gastroenterol 2007; 42 (6): 673-81

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43. Saxena A, Perez H. Pigmented villonodular synovitis about the ankle: a review of the literature and presentation in 10 athletic patients. Foot Ankle Int 2004; 25 (11): 819-26 44. Mitchell IL, Martin DF, Pope TL, et al. Diffuse pigmented villonodular synovitis in a college football player. J South Orthop Assoc 1997; 6 (1): 73-7 45. Hart LE. Exercise and soft tissue injury. Baillieres Clin Rheumatol 1994; 8 (1): 137-48 46. Burckhardt CS, Jones KD, Clark SR. Soft tissue problems associated with rheumatic disease. Lippincotts Prim Care Pract 1998; 2 (1): 20-9 47. Malmivaara A, Viikari-Juntura E, Huuskonen M, et al. Rheumatoid factor and HLA antigens in wrist tenosynovitis and humeral epicondylitis. Scand J Rheumatol 1995; 24 (3): 154-6 48. Jarvinen TA, Kannus P, Paavola M, et al. Achilles tendon injuries. Curr Opin Rheumatol 2001; 13 (2): 150-5 49. Bourikas LA, Kritikos HD, Papakostantinou OG, et al. Chronic alcohol consumption as a predisposing factor for multiple tendon ruptures in unusual sites in a patient with rheumatoid arthritis. Clin Exp Rheumatol 2007; 25 (3): 461-3 50. Lagoutaris ED, Adams HB, DiDomenico LA, et al. Longitudinal tears of both peroneal tendons associated with tophaceous gouty infiltration: a case report. J Foot Ankle Surg 2005; 44 (3): 222-4 51. Ariyoshi D, Imai K, Yamamoto S, et al. Subcutaneous tendon rupture of extensor tendons on bilateral wrists associated with calcium pyrophosphate dihydrate crystal deposition disease. Mod Rheumatol 2007; 17 (4): 348-51 52. Cronin ME. Musculoskeletal manifestations of systemic lupus erythematosus. Rheum Dis Clin North Am 1988; 14 (1): 99-116 53. Swigart C, Scott W. Hand and wrist pain. In: Harris Jr ED, Budd R, Genovese M, et al., editors. Kelley’s textbook of rheumatology. Vol. I. 7th ed. Philadelphia (PA): Elsevier Science 2005: 623-36

Correspondence: Prof. Michael Fredericson, Division of Physical Medicine and Rehabilitation, Department of Orthopaedic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Edwards Building #R107, Stanford, CA 94305-5336, USA. E-mail: [email protected]

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Physiological Responses of Sickle Cell Trait Carriers during Exercise Philippe Connes,1 Harvey Reid,2 Marie-Dominique Hardy-Dessources,3 Errol Morrison4 and Olivier Hue1 1 Laboratory ACTES UPRES-EA 3596, Department of Physiology, University of the French West Indies, Campus de Fouillole, Pointe-a`-Pitre, Guadeloupe, French West Indies 2 Department of Basic Medical Sciences (Physiology Section), Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica, West Indies 3 Inserm, U763, University of the French West Indies, Pointe-a`-Pitre, Guadeloupe, French West Indies 4 University of Technology, Jamaica, Kingston, Jamaica, West Indies

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Sickle Cell Trait (SCT) and Anaerobic Performance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Epidemiological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Laboratory Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. SCT and Aerobic Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Epidemiological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Laboratory Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. The Paradox of Lactic Response: A Controversial Issue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Hypolactacidaemia, Normolactacidaemia or Hyperlactacidaemia during Exercise?. . . . . . . . 4. SCT, Clinical Risk and Exercise-Related Sudden Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Medical Complications and SCT: Fiction or Reality?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Exercise Sudden Death and SCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Putative Causes of Exercise Sudden Death in SCT Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

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Growing evidence suggests that physiological responses during exercise in sickle cell trait (SCT) carriers might differ from persons with normal haemoglobin. Epidemiological and experimental results support the view that SCT carriers could be advantaged in certain anaerobic activities, but the underlying physiological and bio-cellular mechanisms remain unknown. Maximal aerobic physical fitness (i.e. maximal oxygen consumption and maximal aerobic power) is not affected by SCT; however, recent studies suggest that SCT carriers could be characterized by a lesser aerobic capacity. Discrepancies are frequently reported in the literature concerning lactate metabolism during exercise in this population. While some studies observed higher blood lactate concentration during exercise in individuals carrying SCT compared with subjects with normal haemoglobin, others described lower concentration, which suggests a paradoxical lower lactate production by exercising muscles and/or greater ability to clear circulating lactate in SCT

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carriers. One of the most debated topics is the clinically benign condition of SCT, particularly during strenuous exercise. SCT carriers are usually involved in physical exercise without developing medical complications; however, several authors have presented case reports of SCT carriers who have collapsed and died unexpectedly during or after exercise. Blood rheological, haemostatic and vascular adhesion mechanism abnormalities in combination with environmental factors, such as heat strain, might play a role in the occurrence of these fatal scenarios. Several physiological differences have been observed between SCT carriers and non-SCT carriers, which make it necessary to consider the former as a specific population in response to exercise.

Sickle cell anaemia (SCA or SS homozygous sickle cell disease) is an inherited blood disorder caused by a single point mutation in one of the genes encoding haemoglobin. This mutation results in the substitution of valine for glutamic acid in the sixth residue of the b chain leading to the presence of haemoglobin S (HbS), instead of HbA, in the red blood cells (RBCs). When RBCs from patients with SCA become deoxygenated in the capillaries, the HbS may polymerize, inducing the sickling process and giving rise to elongated crescent shape or sickled RBCs. Other factors such as lowered pH, RBC dehydration and hyperthermia are also known to prompt sickling. The sickled cells are rigid and hence poorly deformable, thus failing to negotiate the small channels of the microcirculation. The marked reduction in RBC deformability results in stasis in the microvasculature. The abnormal rheology of the sickle cells may be associated with inflammatory phenomena, which can contribute to the development of hypoxia, vaso-occlusive crisis and organ damage. Moreover, these rigid RBCs are more fragile than normal RBCs, and are prone to haemolytic episodes, often leading to anaemia. Sickle cell trait (SCT), in contrast, is the heterozygous form of SCA, which is marked by the presence of both HbS and HbA. Its prevalence is between 20% and 40% in the Black population of Africa,[1] 8–10% for African Americans[2] and 10% in the Caribbean Islands.[3] SCT, in contrast to SCA, is usually considered a benign disorder[4] and the longevity and morbidity of ª 2008 Adis Data Information BV. All rights reserved.

SCT carriers seems to compare favourably with subjects with HbA.[5] Although SCT is assumed to be benign, under unusual circumstances, more frequently in athletes and army recruits, it has been associated with the development of various forms of vasoocclusive events, often leading to death.[6-19] Therefore, several studies have been carried out to assess the ability of SCT carriers to perform different types of exercise of varying intensity and to compare the physiological responses with a control population who have the normal haemoglobin genotype HbAA. One of the first reports of SCT carriers participating in high-level sports was in the Mexico Olympic Games in 1968.[20,21] The authors investigated the association between athletic ability and single gene systems.[21] Although the study failed to demonstrate any relationships between athletic ability and a single gene system, the authors reported that ‘‘a sizeable number of Negroid Olympic athletes manifested the sickle cell trait.’’[21] Additionally, Le Gallais et al.[22] and Thiriet et al.[23] reported a prevalence of 13.7% and 18.6% SCT carriers in physical education and sports colleges in Ivory Coast and Cameroon, respectively. In other words, the percentages were similar to those observed in the general population of both countries. Therefore, SCT did not seem to be a limiting factor for participating in sports. However, different research findings support the view that SCT carriers could be advantaged or disadvantaged during exercise, depending Sports Med 2008; 38 (11)

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on the dominant energy pathway contributing to the re-synthesis of adenosine triphosphate (ATP).[24-30] This article reviews the physiological responses of SCT carriers during physical exercise. First, we focus on epidemiological and experimental results demonstrating an advantage of SCT carriers for certain anaerobic exercise. This is followed by the epidemiological and experimental works showing any limitation of SCT carriers in performing endurance exercise. Thirdly, we examine the paradox of lactic response in SCT carriers during exercise. Finally, the medical complications and possible mechanisms of exercise-related sudden death in SCT subjects are discussed. 1. Sickle Cell Trait (SCT) and Anaerobic Performance 1.1 Epidemiological Studies

Le Gallais et al.[31] reported the presence of one athlete with SCT during the semi-final of the 4 · 400 m in the Los Angeles Olympic Games of 1984. A large epidemiological study made on Ivory Coast track-and-field throw and jump champions between 1956 and 1995 demonstrated a higher percentage of SCT carriers, as compared with the percentage in the general population, suggesting that SCT might be a contributing factor for success in brief and explosive trackand-field events involving mainly anaerobic metabolism.[32] Thirty-four (27.8%) SCT carriers were identified among the 122 national champions studied; they won 78 national titles (24.5%) and established 37 national records (43.5%), distributed among the throw and jump events.[32] Interestingly, the women’s high-jump and men’s shot-put events had the highest percentages of SCT carrier record holders (90.9% and 87.5%, respectively). Indeed, it has been hypothesized that SCT could constitute an advantage in practicing anaerobic exercise at a very high competitive level. Le Gallais et al.[24] analysed the exercise performance in SCT carriers during the different National Ivory Coast athletic sports events and reported that SCT carriers established 32 of ª 2008 Adis Data Information BV. All rights reserved.

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33 national records on running courses less than 400 m, suggesting a greater ability of SCT carriers to perform in short and intense running events than in endurance courses. Marlin et al.[33] observed a high prevalence of SCT carriers in the French National sprint team in 2000 (i.e. 18.75%), and the percentage of titles and records held by the SCT carriers was significantly higher than for the non-carriers (38.6% and 50% for men and women with SCT, respectively). These observations led several researchers to design laboratory studies to test whether anaerobic performance was greater in SCT carriers than in non-SCT carriers. 1.2 Laboratory Studies

A limited number of studies have examined anaerobic metabolism in SCT subjects using different exercise protocols. Overall, the findings have been controversial. Several authors hypothesized that the low affinity of HbS for oxygen within SCT carriers’ RBCs might cause repeated episodes of tissue hypoxia, causing exercising muscles to develop anaerobic capacity to compensate for the hypothetically low oxidative capacity.[29,34] It has been previously shown that repeated hypoxia may favour type II muscle fibre formation.[35] However, comparison of anaerobic performance and anaerobic metabolism (i.e. peak anaerobic power, maximal velocity, maximal braking force, blood lactate kinetics during exercise and recovery) during a force-velocity test between SCT carriers and a control group showed no significant difference between the two groups.[29] This result has been recently confirmed using another method to assess peak anaerobic power during a single 10-second cycling sprint.[27] The latter group of researchers also reported that the anaerobic work developed during the cycling sprint test did not differ between the two groups. Therefore, subjects with SCT and controls with normal haemoglobin seem to have similar anaerobic exercise performance and similar anaerobic exercise metabolism. These data do not confirm the hypothetical higher anaerobic metabolism suggested in subjects with SCT.[29] Sports Med 2008; 38 (11)

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In contrast, SCT carriers have been shown to reach higher performance during a jumpand-reach test than control subjects.[26] This result is in agreement with epidemiological studies showing greater percentages of SCT carriers as title holders (27.3%) and record holders (41.9%) in extremely brief and intense exercise,[32] but contrasts with the findings of Bile´ et al.[29] and Connes et al.[27] However, the exercise protocols used in these studies[27,29] are mainly dependent on the lactic anaerobic metabolism.[36] Jones et al.[37] noted that the energy required during fast-speed cycling was provided from instantly available ATP in muscle, the phosphocreatine system and anaerobic glycolysis. Despite the shortness of the force-velocity test, the anaerobic metabolism involved must be considered as both alactic and lactic.[37] The jump-and-reach test used in the study of Hue et al.[26] is considered as an exclusive alactic anaerobic test.[38] Thus, it appears that SCT carriers are not disadvantaged in extremely brief and intense exercise involving mainly alactic anaerobic metabolism. When exercise involves both alactic and lactic anaerobic metabolism, SCT carriers and subjects with normal haemoglobin had the same level of performance. Hue et al.[26] did not find any difference between SCT carriers and controls on a 100-m sprint, as previously shown by Le Gallais et al.[34] Many team sports require the participants to repeatedly produce maximal or near-maximal sprints of short duration (<6 seconds) interspersed with brief recovery periods, over an extended period of time.[39,40] The latter group developed an exercise test to assess the repeated sprint ability (RSA test) of sports athletes, which consisted of five 6-second maximal cycling sprints interspersed with 24 seconds of passive recovery. The same test was used to compare the performance between a group of SCT carriers and a control group[27] and showed that both groups were able to repeat successive sprints. However, the pattern of repeated maximal sprint performance was markedly different between the two groups. Although the overall work developed during the entire test was similar in the two groups, SCT carriers were not able to maintain the same maximal performance during the ª 2008 Adis Data Information BV. All rights reserved.

successive sprints. This result contrasts with a previous study performed by Gozal et al.,[41] who examined the exercise performance of SCT carriers and control subjects during a series of four, 2-minute, maximal cycle exercise tests separated by 20 minutes of passive or active recovery. They did not observe any differences between the two populations. They therefore concluded that the presence of HbS in RBCs does not affect repeated maximal exercise performance requiring predominantly anaerobic contribution. Finally, the lack of difference in the latter study might be explained by the long recovery period, which allowed effective recovery in SCT carriers. The study of Connes et al.[27] suggested that SCT carriers probably need longer time than controls to recover completely from a single anaerobic exercise to be able to repeat the same performance. Longer recovery could allow: (i) better re-oxygenation of HbS; and (ii) greater clearance of lactic acid, which could reduce the risks for sickling. 2. SCT and Aerobic Performance 2.1 Epidemiological Studies

Several studies have suggested that SCT is not a limiting factor to practice physical activities requiring aerobic metabolism. For example, it has been reported that 6.7% of Black football players in the National Football League were SCT carriers[42] and 10.5% of Black high-school athletes had SCT in football and basketball.[43] In addition, Thiriet et al.[44] reported that the prevalence of SCT carriers during the International Mount Cameroon Ascent Race (a 34.1-km race over difficult terrain with a strong aerobic component, slopes ranging from 7% to 40%, and altitudes varying from 615 to 4095 m) was similar to the ethnically corrected SCT prevalence in the general population. Finally, in 1506 Black males participating in the first Abidjan semi-marathon, SCT was detected in 8.7%, a percentage similar to that observed in the general Ivory Coast population.[25] These combined results led Le Gallais et al.[19] to state that there is no selective exclusion of individuals with SCT from participation in Sports Med 2008; 38 (11)

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aerobic sports/activities. However, although the percentage of participation of SCT carriers in the Abidjan semi-marathon was similar to the prevalence of SCT found in the general population, the only SCT athlete who was internationally ranked also had heterozygous a-thalassaemia.[25] a-Thalassaemia is known to cause haematological changes, such as microcytosis[45] and haemorheological changes, e.g. improved RBC deformability.[46] These changes would be expected to improve tissue oxygenation and, hence, aerobic performance. Additionally, Thiriet et al.[44] observed few SCT carriers among the Bakoueri tribe runners (a tribe that confers elevated social prestige to good performance times in the races) during the Mount Cameroon Ascent Race (i.e. 2.4% vs 15.6% in the general Bakoueri population). Indeed, although SCT carriers are able to practice certain aerobic activities, it seems that they may not be able to train or compete at the same high level as subjects with normal haemoglobin. 2.2 Laboratory Studies

Several studies have compared the aerobic physical fitness of SCT carriers with that of control subjects. It has been hypothesized that SCT carriers have lower aerobic ability than subjects with normal haemoglobin because, within the RBCs, HbS has a lower affinity for oxygen than HbA.[47] Also, there are marked differences in whole-blood rheology, both at rest and during exercise, between SCT carriers and non-carriers.[46,48-53] Furthermore, disturbance of blood rheology is known to impair tissue oxygenation[54,55] and aerobic physical fitness.[56-58] Therefore, SCT carriers are expected to have a lower aerobic physical fitness than similar subjects with normal haemoglobin. Cresta[59] reported no difference in the energy expenditure of SCT carriers and non-carriers during a progressive and maximal exercise test. In 1976, Robinson et al.[60] compared the total treadmill time, maximal oxygen consumption . (VO2max), maximal heart rate and heart rate during recovery of 16 Black SCT males and 16 non-SCT males in response to a ramp exercise ª 2008 Adis Data Information BV. All rights reserved.

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test and found no difference between the two groups. Resting pulmonary function and cardiopulmonary performance during exercise to exhaustion were also found to be similar in SCT carriers and control subjects who had resided at moderately high altitude (‡1609 m above sea level) for at least 10 years.[61] Similarly, Le Gallais et al.[31] observed no significant difference between SCT and non-SCT carriers in the maximal aerobic power (MAP) output reached during a graded exercise test conducted until exhaustion. A series of studies have investigated the effects of mild hypoxia (1270 m), moderate simulated hypoxia (2300 m) and severe simulated hypoxia (4000 m) on cardiopulmonary responses during steady-state and ramp exercise in SCT carriers and control subjects.[62-65] However, no differences in cardio-ventilatory parameters were found between the SCT carriers and controls. Although cumulative effects of exercise and light to severe hypoxia have been shown to cause sickling of RBCs in SCT . carriers, assessment of oxygen consumption (VO2) during a maximal arm crank exercise test showed no difference between SCT carriers and a control group.[65] This finding was not surprising because when blood leaves exercising muscles, the oxygen partial pressure is decreased and concentrations in lactate, hydrogen ions and other metabolites are increased. The increased concentration of these metabolites favours sickling of RBCs in SCT carriers. The numbers of sickled RBCs that leave the exercising muscles are likely to be greater than the number of sickled cells entering the exercising muscles since the partial pressure of oxygen is greater in the pre- than in the postcapillary venules and veins. Therefore, Martin et al.[65] concluded that sickling in the effluent blood of an exercising limb does not appear to measurably affect overall maximal arm crank exercise performance. An alternative explanation could be that, within the erythrocytes, the lower affinity of HbS for oxygen compared with HbA, particularly at low arterial partial pressure of oxygen (such as in muscle capillaries), could favour the delivery of oxygen to tissues that might compensate for the presence of low deformable RBCs, known to disturb blood flow Sports Med 2008; 38 (11)

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in the microcirculation.[54,55] However, this assumption is not supported by the observations made by Hardy et al.[66] They reported greater venous blood pressure and saturation of oxygen (i.e. greater oxygen content) in SCT carriers compared with subjects having normal haemoglobin during a treadmill exercise at all time intervals, suggesting microvascular shunting in SCT carriers and decreased peripheral utilization of oxygen. Microvascular shunting in SCT carriers could compensate for microvascular blockage due to altered blood rheology in that population.[46,52] In a parallel study, Weisman et al.[64] observed the same arterial oxygen tension between SCT carriers and controls during progressive and maximal exercise performed at an altitude of 1270 m. Consequently, the decreased (suggested) peripheral utilization of oxygen in SCT carriers was caused neither by hypoxaemia nor compensation by higher arterial oxygen content. Nevertheless, although SCT carriers might experience decreased muscular oxygen utilization . during exercise, they do not have impaired VO2max, MAP or anaerobic threshold (AT).[31,41,46,60,61,63,64,67-71] According to the Fick . equation, VO2 depends on the cardiac output (CO) and the arterial-venous oxygen content difference (CaO2-CvO2). Therefore, one may hypothesize that SCT carriers could have greater CO than non-carriers to compensate for the lower arterial-venous oxygen content difference . and to exhibit normal VO2max.[72] To the best of our knowledge, no study has yet investigated the kinetics of CO during incremental exercise test in SCT carriers. And, although SCT carriers and controls usually exhibit similar heart rate in response to exercise, it is difficult to say whether an increased CO in SCT carriers could compensate for a putative alteration in blood oxygen transport to the muscles. . Although maximal aerobic physical fitness (VO2max and MAP) and ventilatory/lactic thresholds assessed during progressive and maximal exercise tests are not different between SCT carriers and similarly trained subjects with normal haemoglobin, some findings suggest that SCT carriers could be at a disadvantage when performing prolonged and submaximal endurance ª 2008 Adis Data Information BV. All rights reserved.

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exercise. Indeed, Le Gallais et al.[31] reported poor cardioventilatory adaptation in SCT carriers compared with non-carriers during a 45minute square-wave endurance exercise test. This test consisted of a succession of nine bouts of 5-minute exercise (4 minutes performed at the aerobic threshold intensity plus 1 minute supramaximal effort). During the Mount Cameroon Ascent Race, Thiriet et al.[44] recorded similar performance times for SCT and non-SCT runners, except during the segment of the race in which altitude ranged from 3800 to 4095 m. During the high-altitude segment, the authors reported significantly longer times in SCT runners, suggesting that prolonged aerobic efforts, particularly in hypobaric hypoxic conditions, may be associated with a deleterious effect on performance in SCT; a finding that contrasts with previous results.[62-64] However, Weisman and colleagues’ studies[62-64] were performed on a ramp exercise test conducted until exhaustion in the laboratory and lasted only a few minutes, whereas Thiriet et al.[44] tested the endurance capacity of SCT carriers during a prolonged and intense effort conducted for several hours in a mountainous terrain. Connes et al.[28] recently examined the kinetics . . of VO2 (fast and slow component of VO2 kinetics) during a transition from rest to constant work-rate exercise performed at 70% of the MAP in a group of SCT carriers (n = 6), a group of SCT carriers with a-thalassaemia (n = 9) and a control group (n = 10). The authors observed that athletes with SCT (with or without associated a-thalassaemia) and athletes with normal haemoglobin . did not show significant differences in VO2 onkinetics response at the early onset of a constant work-rate submaximal exercise bout (i.e. fast . component of VO2 kinetics) suggesting normal adaptation during the first minutes of one aerobic exercise.[28] After this initial phase, the two groups of SCT athletes had one-third greater slow component amplitude than control subjects, suggesting lower aerobic capacity and greater exercise intolerance in SCT carriers during prolonged and intense submaximal exercise. The physiological mechanisms underlining the greater . VO2 slow component in SCT carriers are Sports Med 2008; 38 (11)

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unknown. Further studies are therefore needed to address this issue. 3. The Paradox of Lactic Response: A Controversial Issue 3.1 Hypolactacidaemia, Normolactacidaemia or Hyperlactacidaemia during Exercise?

Most of the investigations of maximal aerobic . physical fitness (i.e. VO2max and MAP) in SCT carriers during incremental exercise tests also studied the lactic acid response.[41,46,67-69,73,74] In . addition to the hypothetically impaired VO2max in SCT carriers, several investigators suggested that lactic acid response should be greater in SCT carriers during exercise compared with non-carriers.[73,75] Freund et al.[73] investigated the ability of SCT carriers to exchange and remove lactate from the circulation after a ramp exercise test (i.e. during recovery) using a mathematical model based on the study of the lactate recovery curves. Their results suggested that SCT carriers were likely to either produce more lactate than controls or to have an impaired ability to clear circulating lactate.[73] These authors proposed that the presence of HbS impairs oxygen delivery to muscles during exercise resulting in a greater contribution of anaerobic metabolism to exercising muscles and leading to hyperlactacidaemia.[73,75] However, none of these studies matched SCT carriers and control subjects according to physical activity. Thus, other authors compared the kinetics of lactate levels during and after the same kind of exercise tests between matched SCT carriers and controls.[41,67,69] These studies reported lower lactate levels in SCT carriers during the submaximal stage of exercise, at . VO2max and during the first few minutes of recovery, suggesting lower lactate production by exercising muscles and/or greater ability to clear circulating lactate. These findings contrast with those of Freund et al.[73] The greater activity recently found for the RBC monocarboxylate transporter1 in SCT carriers could contribute to the regulation of lactate exchange between blood and other cellular compartments leading to the development of hypolactacidaemia.[74] Another ª 2008 Adis Data Information BV. All rights reserved.

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recent study conducted in our laboratory investigated the time-course of RBC : plasma lactate concentration ratio and plasma-to-RBC lactate concentration gradient during incremental exercise, which provided information on lactate exchange processes between muscle and blood compartments and among the different blood compartments.[68] The results suggested that lactate production or clearance was similar in SCT carriers and non-carriers.[68] Unfortunately, these conflicting results make it difficult to draw a definitive statement about the lactic acid response and metabolism in SCT carriers during exercise. Greater precautions should be taken in the design of future protocols to allow for valid comparisons between studies. A multicentred study conducted on the lactic response of SCT carriers and using the same methodology may be useful in providing a better understanding of the mechanism involved in the lactic acid response in SCT carriers. 4. SCT, Clinical Risk and Exercise-Related Sudden Death 4.1 Medical Complications and SCT: Fiction or Reality?

Unlike SCA, SCT is usually considered as an asymptomatic benign condition.[4] In addition, Ashcroft et al.[76] and Rehan[77] reported that the presence of SCT did not affect growth and mental development. However, it is now confirmed that SCT carriers are at risk for developing hyposthenuria,[78] haematuria[79] and renal medullary carcinoma, an aggressive carcinoma with unique radiological signs and anatomical and microscopic histology.[80] Moreover, studies in Jamaica, England and America established that the rates of urinary tract infection are higher for women who have SCT than for racially matched controls.[81,82] Several studies also confirmed that SCT carriers are more susceptible to ocular complications following traumatic hyphaema, such as retinal vascular occlusions and secondary glaucoma.[83-85] Rare cases of dactylitis, osteonecrosis of the femoral head and fatal pulmonary infarction, which are common complications in Sports Med 2008; 38 (11)

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SCA, have also been reported in SCT carriers.[86-89] Although highly debatable,[90] some authors considered SCT as a risk factor for stroke.[91,92] Connes et al.[93,94] reported that SCT carriers are marked by impaired autonomic nervous system activity, suggesting that SCT carriers could be predisposed to cardiovascular complications. Cardiac autonomic imbalance indicates severe cardiovascular diseases and predicts a poor outcome.[95] Recent results from Rahimi et al.[96] suggested lower risk factors for coronary artery disease in SCT carriers than in control subjects (i.e. higher high-density lipoprotein cholesterol levels in SCT carriers). However, Ould Amar et al.[97] noted a trend for SCT carriers to develop thrombosis and coronary artery disease. Heller et al.[79] found a statistically significant association between surrogate markers for pulmonary embolism and SCT, but definitive conclusions from this study were not possible because the observation of increased incidence of pulmonary embolism in this population was not adequately substantiated. Austin et al.[98] provided strong evidence of higher risk to develop venous thromboembolism (odds ratio: 1.8) and pulmonary embolism (odds ratio: 3.9) among African Americans with SCT than in non-SCT carriers. This confirms previous findings demonstrating haemostatic perturbations in this population.[99] It has also been proposed that SCT should be considered as a risk factor for microvascular complications in Africans with type 2 diabetes mellitus.[100,101] Reid and Oli[102] demonstrated impaired whole blood filtration in diabetic patients with haemoglobin genotype HbAA when compared with normal non-diabetic controls. However, diabetic patients with SCT showed even more striking rheological abnormalities, as filtration values in these patients were equal to only 36% of the values found in HbAA patients. Nigerian diabetic patients with SCT may have greater risks of developing proteinuria, with renal dysfunction and/or hypertension and probably diabetic nephropathy than their counterparts with haemoglobin genotype HbAA.[103] Biedrzycki et al.[104] recently reported a case of sudden death in a diabetic patient with SCT. The authors stated that ‘‘given the frequency of both SCT and ª 2008 Adis Data Information BV. All rights reserved.

diabetes in the Afro-Caribbean population, it is important for clinicians involved in the treatment of these patients to appreciate that the conditions may frequently coexist and sickle cell (trait) patients may have a precipitous clinical decline.’’ Reid and Famodu[105] explained that the percentage of HbS in RBCs is highly variable from one SCT carrier to another, depending on the association or not with a-thalassaemia, and that the possible clinical importance of erythrocyte HbS level is apparently not yet appreciated. This may be because people with SCT are mainly asymptomatic, although a small percentage has often been known to complain of generalized ‘crisis’ pains. These persons may have HbS levels either in the upper range or exceeding the upper limit of normal. It may not be an overstatement to suggest that the proportion of HbS in SCT carriers may be as important clinically as the level of fetal haemoglobin in people with SCA. Therefore, although SCT carriers are usually in good health[4] and direct causal relationships between SCT and the observed medical complications are difficult to prove, most of these studies suggest that medical and clinical surveys of this population could be reinforced compared with current practice.

4.2 Exercise Sudden Death and SCT

One of the most debated topics concerning the medical complications of SCT carriers is episodes of exercise-related sudden death.[18,19,106] Several authors have presented case reports of SCT carriers who have collapsed and died unexpectedly; nearly always under conditions of extreme exertion.[6-12,14-17,81,107-114] Recent evidence indicated that SCT continues to be the leading cause of sudden death for young African Americans in military-based training and civilian organized sports.[2] The death of ten college football players and three US army recruits between 1974 and 2000 were strongly suspected to be associated with SCT. For Mitchell,[2] the penal military-style boot camps in the US and the recent death of two Sports Med 2008; 38 (11)

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teenagers with SCT merits renewed vigour in the education of athletic instructors, the military and the public about conditions associated with sudden death in individuals with SCT. The National Athletic Trainers’ Association (NATA) in the US recently recommended that colleges and high schools show greater awareness of the typically benign condition, which poses a grave risk during intense exertion of physical activity. A task force consensus recommends confirming SCT status in all athletes’ pre-participation physical examinations and provides details on measures that can reduce the risk of collapse related to SCT among athletes during sports and exercise.[115] Kark et al.[14] performed a complete cohort study of exercise-related death among the 2 087 600 people who entered the US Armed Forces basic enlisted military training during a 5-year period (1977–81). There were 37 300 Black recruits with SCT, 1300 non-Black recruits with SCT, 429 000 Black recruits without SCT, and 1 620 000 non-Black recruits without SCT. Fortyone exercise-related deaths occurred. Risk ratios were examined among the Black recruits, ignoring the small number of non-Blacks with SCT. The relative risk of exercise-related death explained by pre-existing disease (largely silent heart disease) was 2.3 for SCT, but this was not statistically significant. The relative risk of exercise-related death unexplained by pre-existing disease was 28 for SCT. The excess exerciserelated death with SCT was likely to result from the immediate stress of exercise. About 50% of the deaths resulted from heat illness due to overexertion and the remaining cases were idiopathic sudden deaths. Clinical features and distribution of cases between heat illness and idiopathic sudden deaths did not differ by the presence or absence of HbS, except that rhabdomyolysis was the predominant form of exertional heat illness among cases with SCT.[15] Although the causal relationship between SCT and these medical complications has not been confirmed, these reports have introduced doubts about the medical status of SCT carriers.[116] Consequently, Ajayi[117] has recently proposed that SCT has been misclassified as benign and ª 2008 Adis Data Information BV. All rights reserved.

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asymptomatic and should be reclassified as a disease state. Lucas[118] underlined two clinico-pathological patterns that have emerged from the different case reports of exercise-related sudden death of SCT carriers, namely: (i) patients who developed exertional rhabdomyolysis; and (ii) patients who did not develop rhabdomyolysis. SCT carriers who developed rhabdomyolysis collapsed with marked metabolic acidosis, lactic acidaemia, myoglobinuria, renal failure and disseminated intravascular coagulation. In 1972, a 22-year-old African American military recruit with SCT suddenly collapsed after running 3 miles (4.8 km).[9] He complained of muscle tenderness over the abdomen, back and extremities within 4 hours after exercise. Despite immediate treatment for acute renal failure and exertional rhabdomyolysis, the subject died 48 hours later. Two cases of exertional rhabdomyolysis with renal failure with death ensuing have been reported in Black military recruits after running.[108,109] Rosenthal and Parker[110] reported the case of a 22-year-old football player with SCT who suddenly collapsed after completing an 800-m run. Despite immediate and aggressive treatment for exertional rhabdomyolysis, the patient died 46 hours after his collapse.[110] Lucas[118] noted that when autopsy was performed on SCT carriers who had died after exertional rhabdomyolysis, widespread multi-organ small vessel sickling was seen and the lungs often had typical histopathology of acute chest syndrome.[108,111,112,119] It is not fully understood whether SCT itself or some other unidentified, but associated, metabolic defect constitutes a small subgroup of SCT carriers who are more susceptible to the development of exertional rhabdomyolysis. Sherry[120] proposed that exercise alone is not sufficient to precipitate the cascade of events leading to such a scenario in persons with SCT. He hypothesized that dehydration might contribute to the development of sickling in muscle capillaries and that SCT carriers might be naturally more predisposed to dehydration due to their inability to concentrate their urine when deprived of water.[120] This defect might make SCT carriers less able to conserve water than non-carriers. Sports Med 2008; 38 (11)

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If true, a higher amount of water intake should be required for exercising SCT carriers compared with control subjects. Other patients who do not exhibit rhabdomyolysis collapse and who show widespread sickling, often with small infarcts in many organs, are presumed to have died of multi-organ failure of which the most important insult was cardiopulmonary arrest.[14,118,121,122] Metabolic or environmental changes such as hypoxia, acidosis, dehydration, hyperosmolality or hyperthermia may induce polymerization of HbS and, hence, transform silent SCT into a syndrome resembling sickle cell disease with vaso-occlusive crises.[15] Several biocellular and biochemical factors may be involved in sickle cell crises of SCA patients such as disturbed blood rheology, hypercoagulation and decreased fibrinolysis, amplified inflammatory and vascular adhesion phenomenon.[123-132] Indeed, several studies compared the evolution of these factors during exercise between SCT carriers and normal subjects in an attempt to understand why SCT carriers could be more prone to exercise sudden death. 4.3 Putative Causes of Exercise Sudden Death in SCT Carriers

Surprisingly few studies have investigated the balance between haemostasis and fibrinolysis in SCT carriers during exercise. Westerman et al.[99] reported increased levels of d-dimers, thrombinantithrombin complexes and prothrombin fragment 1.2 in SCT carriers at rest compared with matched control subjects that suggested increased coagulation activity in the SCT group population. These results contrast with recent results obtained by Awodu and Famodu[133] who compared haematocrit, erythrocyte sedimentation rate, platelet count, fibrinogen and factor VII in resting conditions between SCT carriers and non-carriers and found no difference. However, these authors did not assess these markers during exercise and it is difficult to draw conclusions about a putative role of haemostatic perturbations in exercise-related sudden death in SCT carriers. Connes et al.[134] measured ª 2008 Adis Data Information BV. All rights reserved.

coagulation markers, including prothrombin time, activated partial thromboplastin time, plasma fibrinogen, antithrombin III activity, haematocrit and yield stress in SCT carriers and control subjects at rest and at the end of a progressive and maximal exercise test. Blood coagulation markers, haematocrit and yield stress were not different between the two groups at rest. At the end of exercise, these parameters, except for plasma fibrinogen, which was slightly higher in SCT carriers, but in the normal range, were not significantly different between the two groups. It could therefore be implied from these results that the increased risk for clinical complications in certain SCT carriers during exercise is not related to an increased blood coagulation activity. Further studies are clearly warranted to examine the balance between haemostatic factors and fibrinolytic activity in SCT carriers. Few studies have investigated inflammatory markers and adhesive molecules in SCT carriers and non-carriers. Duits et al.[135] compared the resting levels of cytokines (interleukin-6 and granulocyte-macrophage colony-stimulating factor) and soluble adhesion molecules (E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) between control subjects, SCT carriers and sickle cell disease patients with SC and SS genotypes. No difference was found between SCT carriers and control subjects, suggesting the absence of a marked inflammatory phenomenon in SCT. Nevertheless, results have been recently published showing greater levels of soluble VCAM-1 in SCT carriers at rest compared with subjects with normal haemoglobin, despite similar levels of ICAM-1 and tumour necrosis factor-a in plasma for the two groups.[136] It remains unclear why Monchanin et al.[136] found increased levels of soluble VCAM-1 in SCT carriers without increased levels of soluble ICAM-1. The authors also assessed the kinetics of these three markers in response to a progressive and maximal exercise test and observed that exercise increased VCAM-1 in the two groups, but VCAM-1 remained raised only in SCT carriers during the recovery period. Indeed, it was concluded that Sports Med 2008; 38 (11)

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SCT carriers might be at risk for microcirculatory disturbances and adhesive phenomena developing at rest and several hours after exercise.[136] However, Monchanin et al.[136] did not make corrections of their values by taking into account the plasma volume variations during exercise. Therefore, conclusions made by Monchanin et al.[136] have to be viewed with caution. Besides, recent results obtained by our group[137] showed that strenuous exercise did not change the concentrations of either soluble VCAM-1 or ICAM-1 in SCT carriers and subjects with normal haemoglobin when plasma volume variations due to exercise were taken into account. Additionally, resting concentrations of VCAM-1 and ICAM-1 were not different between the two groups. These results reinforced earlier findings by Duits et al.,[135] but contrasted with the recent results of Monchanin et al.[136] Thus, further investigations are required to test the evolution of inflammatory markers and adhesion molecules in SCT carriers and control subjects in response to different kinds of exercise. This will provide information about the possible involvement of these factors in the exercise-related sudden death of SCT carriers. The last factor playing a role in vaso-occlusive crisis in patients with SCA is blood rheology.[130] Therefore, haemorheologists have investigated blood rheology changes in SCT carriers in resting conditions and reported lower RBC deformability,[46,48,49,51,52] increased RBC aggregation[50] and higher blood viscosity[52,53] compared with subjects with normal haemoglobin. Impaired blood rheology at rest could be involved in the higher risk of SCT carriers to develop venous thromboembolism.[98] Monchanin et al.[46] assessed blood rheological parameters at rest and during exercise in SCT carriers (with and without a-thalassaemia) and a control group. Exercise decreased RBC rigidity in the three groups, but SCT carriers without a-thalassaemia had higher RBC rigidity than control group and SCT carriers with associated a-thalassaemia at each stage of exercise. Twenty-four hours later, RBC rigidity increased above baseline levels in all groups leading SCT carriers without a-thalassaemia to reach very high values. The authors concluded ª 2008 Adis Data Information BV. All rights reserved.

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that SCT carriers are prone to higher RBC rigidity, which might lead to haemorheological alterations that may participate in the genesis of microcirculatory disorders, thus causing the dramatic scenario of exercise-related sudden death.[46] Similar results have been recently obtained by Tripette et al.[138] who reported a greater increase in RBC rigidity above resting values in SCT carriers than in subjects with normal haemoglobin during the late recovery after a strenuous exercise consisting of repeating three progressive and maximal exercise tests (i.e. 24 and 48 hours after exercise). However, these alterations seem to be limited by the coexistence of a-thalassaemia; suggesting that the latter may have some haemorheological protective effects in subjects with SCT. Connes et al.[53] examined blood rheology changes in SCT carriers and control subjects in response to a short and supramaximal . exercise test lasting 1 minute (intensity: 110% VO2max). Whole blood viscosity, plasma viscosity, haematocrit and RBC rigidity were assessed at rest, at the end of exercise and at 15, 30 and 60 minutes of recovery. All haemorheological values, except RBC rigidity, were increased above resting values in both groups and these values remained higher until 15 or 30 minutes of recovery compared with resting values. Although no significant difference was observed between the two groups for plasma viscosity and haematocrit, whole blood viscosity and RBC rigidity were higher in the SCT carriers at each interval compared with the control group. This could very well constitute increased risks for microcirculatory complications.[53] Therefore, a short supramaximal and a ramp exercise test may not be completely inoffensive for SCT carriers and the haemorheological perturbations in this population could be implicated in the medical complications observed in response to exercise, particularly during recovery.[46,53] The rheo-fluidifying effect of CO on blood viscosity is rapidly reversed after the cessation of exercise, and the prolonged haemorheological changes that persist during recovery are strongly thought to increase the risk of exercise-related morbidity-mortality in the general population.[139] Sports Med 2008; 38 (11)

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It is possible that co-risk factors, such as heat stress, viral illness, poor physical conditioning and dehydration, have precipitated the occurrence of the fatal complications observed in SCT carriers.[17,106,118] Bergeron et al.[140] demonstrated that fluid ingestion at a rate sufficient to offset a bodyweight deficit may reduce RBC sickling during exercise performed in the heat. We hypothesize that when haemorheological perturbations occur simultaneously with haemostatic perturbations, adhesion vascular phenomenon and one or more of the co-risk factors, the risks for the occurrence of unexpected exercise-related death in individuals with SCT could be greatly increased. Baskurt et al.[106] recently underlined that, because exercise is the most well known physiological condition that consumes vascular autoregulatory reserve to maintain homeostasis, even slight, non-symptomatic, vascular and blood rheology abnormalities in SCT carriers may manifest in response to exercise. Large cohort studies of SCT carriers during exercise need to be conducted to test these hypotheses. 5. Conclusions The aim of this article was to examine the physiological, medical and bio-cellular peculiarities of SCT carriers in response to exercise. As a result of common misconceptions regarding SCT, most individuals with the condition are generally not informed regarding the possible consequences of certain activities such as venturing to high altitudes or participating in overly exertional physical activities in high temperature without sufficient hydration. Of course, SCT carriers, like everyone else, must exercise, but basic recommendations have to be provided by medical staff, physicians and trainers. These should include the wearing of light clothing, starting exercise gradually and ensuring adequate fluid intake during exercise. The last recommendation is particularly important for SCT carriers because it seems that they might be naturally more predisposed to dehydration due to their inability to concentrate their urine when deprived of water.[120] This defect might make ª 2008 Adis Data Information BV. All rights reserved.

SCT carriers less able to conserve water than non-carriers. As recently recommended by the NATA,[115] ‘‘the screening (of the presence or not of SCT) and simple precautions may prevent deaths and help the athlete with SCT thrive in his or her chosen sport.’’ Experimental results suggest that exercise responses in SCT carriers might differ from those in similarly trained subjects with normal haemoglobin, depending on the type of exercise performed (i.e. anaerobic or prolonged and submaximal aerobic activities). Further studies, including muscle biochemical functions and lactic acid metabolism, are needed to provide a better understanding of the underlying mechanisms of these specific adaptations. Acknowledgements No sources of funding were used in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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106. Baskurt OK, Meiselman HJ, Bergeron MF. Re. point: counterpoint. Sickle cell trait should/should not be considered asymptomatic and as a benign condition during physical activity. J Appl Physiol 2007; 103 (6): 2142; author reply 2143 107. Koppes GM, Daly JJ, Coltman Jr CA, et al. Exertioninduced rhabdomyolysis with acute renal failure and disseminated intravascular coagulation in sickle cell trait. Am J Med 1977; 63: 313-7 108. Hynd RF, Bharadwaja K, Mitas JA, et al. Rhabdomyolysis, acute renal failure, and disseminated intravascular coagulation in a man with sickle cell trait. South Med J 1985; 78: 890-1 109. Sarteriale M, Hart P. Unexpected death in a black military recruit with sickle cell trait: case report. Mil Med 1985; 150: 602-5 110. Rosenthal MA, Parker DJ. Collapse of a young athlete. Ann Emerg Med 1992; 21: 1493-8 111. Le Gallais D, Bile A, Mercier J, et al. Exercise-induced death in sickle cell trait: role of aging, training, and deconditioning. Med Sci Sports Exerc 1996; 28: 541-4 112. Kerle KK, Nishimura KD. Exertional collapse and sudden death associated with sickle cell trait. Am Fam Physician 1996; 54: 237-40 113. Gardner JW, Kark JA. Fatal rhabdomyolysis presenting as mild heat illness in military training. Mil Med 1994; 159: 160-3 114. Thogmartin JR. Sudden death in police pursuit. J Forensic Sci 1998; 43: 1228-31 115. NATA. Consensus statement: sickle cell trait and the athlete [online]. Available from URL: http://www.nata. org/statements/consensus/sicklecell.pdf [Accessed 2007 Jun 21] 116. Makaryus JN, Catanzaro JN, Katona KC. Exertional rhabdomyolysis and renal failure in patients with sickle cell trait: is it time to change our approach? Hematology 2007; 12: 349-52 117. Ajayi AA. Should the sickle cell trait be reclassified as a disease state? Eur J Intern Med 2005; 16: 463 118. Lucas S. The morbid anatomy of sickle cell disease and sickle cell trait. In: Okpala I, editor. Practical management of haemoglobinopathies. Oxford: Blackwell Publishing Ltd, 2004 119. Murray MJ, Evans P. Sudden exertional death in a soldier with sickle cell trait. Mil Med 1996; 161: 303-5 120. Sherry P. Sickle cell trait and rhabdomyolysis: case report and review of the literature. Mil Med 1990; 155: 59-61 121. Dudley Jr AW, Waddell CC. Crisis in sickle cell trait. Hum Pathol 1991; 22: 616-8 122. Charache S. Sudden death in sickle trait. Am J Med 1988; 84: 459-61 123. Chien S, Usami S, Bertles JF. Abnormal rheology of oxygenated blood in sickle cell anemia. J Clin Invest 1970; 49: 623-34 124. Gordon PA, Breeze GR, Mann JR, et al. Coagulation fibrinolysis in sickle-cell disease. J Clin Pathol 1974; 27: 485-9

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125. Famodu AA. Plasma fibrinolytic activity in sickle cell disease. Trop Geogr Med 1988; 40: 331-3 126. Nash GB, Boghossian S, Parmar J, et al. Alteration of the mechanical properties of sickle cells by repetitive deoxygenation: role of calcium and the effects of calcium blockers. Br J Haematol 1989; 72: 260-4 127. Kaul DK, Nagel RL. Sickle cell vasoocclusion: many issues and some answers. Experientia 1993; 49: 5-15 128. Nsiri B, Gritli N, Bayoudh F, et al. Abnormalities of coagulation and fibrinolysis in homozygous sickle cell disease. Hematol Cell Ther 1996; 38: 279-84 129. Nsiri B, Gritli N, Mazigh C, et al. Fibrinolytic response to venous occlusion in patients with homozygous sickle cell disease. Hematol Cell Ther 1997; 39: 229-32 130. Ballas SK, Mohandas N. Sickle red cell microrheology and sickle blood rheology. Microcirculation 2004; 11: 209-25 131. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet 2004; 364: 1343-60 132. Okpala I. Leukocyte adhesion and the pathophysiology of sickle cell disease. Curr Opin Hematol 2006; 13: 40-4 133. Awodu OA, Famodu AA. Haemostatic variables and their relationship to body mass index and blood pressure in adult Nigerians with the sickle cell trait. Clin Hemorheol Microcirc 2007; 36: 89-94 134. Connes P, Tripette J, Chalabi T, et al. Effects of strenuous exercise on blood coagulation activity in sickle cell trait carriers. Clin Hemorheol Microcirc 2008; 38: 13-21 135. Duits AJ, Pieters RC, Saleh AW, et al. Enhanced levels of soluble VCAM-1 in sickle cell patients and their specific

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136.

137.

138.

139.

140.

increment during vasoocclusive crisis. Clin Immunol Immunopathol 1996; 81: 96-8 Monchanin G, Serpero LD, Connes P, et al. Effects of a progressive and maximal exercise on plasma levels of adhesion molecules in athletes with sickle cell trait with or without a-thalassemia. J Appl Physiol 2007; 102: 169-73 Tripette J, Connes P, Hedreville M, et al. Patterns of exercise-related inflammatory response in sickle cell trait carriers. Br J Sports Med. In press Tripette J, Hardy-Dessources MD, Sara F, et al. Does repeated and heavy exercise impair blood rheology in carriers of sickle cell trait? Clin J Sport Med 2007; 17: 465-70 Senturk UK, Yalcin O, Gunduz F, et al. Effect of antioxidant vitamin treatment on the time course of hematological and hemorheological alterations after an exhausting exercise episode in human subjects. J Appl Physiol 2005; 98: 1272-9 Bergeron MF, Cannon JG, Hall EL, et al. Erythrocyte sickling during exercise and thermal stress. Clin J Sport Med 2004; 14: 354-6

Correspondence: Dr Philippe Connes, Laboratoire ACTES (EA 3596), De´partement de Physiologie, Universite´ des Antilles et de la Guyane, Campus de Fouillole, 97159 Pointe-a`-Pitre, Guadeloupe, French West Indies. E-mail: [email protected]

Sports Med 2008; 38 (11)

Sports Med 2008; 38 (11): 947-969 0112-1642/08/0011-0947/$48.00/0

REVIEW ARTICLE

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The Inflammatory Response to Skeletal Muscle Injury Illuminating Complexities Carine Smith, Maritza J. Kruger, Robert M. Smith and Kathryn H. Myburgh Department of Physiological Sciences, Stellenbosch University, Matieland, South Africa

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Responses to Skeletal Muscle Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Inflammation, Leucocyte Infiltration and Secondary Damage. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.1 Vascular Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2 Extravasation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.3 Secondary Damage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Resolution of Muscle Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1 Additional Roles for Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2 Inflammatory Cytokine and Growth Factor Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Injury Models – Technical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Invasiveness of Injury Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Details of Drop-Mass Weight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Selection of Muscle Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Contractile Status of the Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Immune-Related Studies Using Contusion Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Cytokine Focus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Other Possible Treatment Options Investigated . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Contusion Injury: the Ideal Model for Injury Research? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

947 950 951 951 951 953 953 954 955 957 957 959 960 961 961 961 962 963 964

Injury of skeletal muscle, and especially mechanically induced damage such as contusion injury, frequently occurs in contact sports, as well as in accidental contact sports, such as hockey and squash. The large variations with regard to injury severity and affected muscle group, as well as nonspecificity of reported symptoms, complicate research aimed at finding suitable treatments. Therefore, in order to increase the chances of finding a successful treatment, it is important to understand the underlying mechanisms inherent to this type of skeletal muscle injury and the cellular processes involved in muscle healing following a contusion injury. Arguably the most important of these processes is inflammation since it is a consistent and lasting response. The inflammatory response is dependent on two factors, namely the extent of actual physical damage and the degree of muscle vascularization at the time of injury. However, long-term antiinflammatory treatment is not necessarily effective in promoting healing, as

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indicated by various studies on NSAID treatment. Because of the factors named earlier, human studies on the inflammatory response to contusion injury are limited, but several experimental animal models have been designed to study muscle damage and regeneration. The early recovery phase is characterized by the overlapping processes of inflammation and occurrence of secondary damage. Although neutrophil infiltration has been named as a contributor to the latter, no clear evidence exists to support this claim. Macrophages, although forming part of the inflammatory response, have been shown to have a role in recovery, rather than in exacerbating secondary damage. Several probable roles for this cell type in the second phase of recovery, involving resolution processes, have been identified and include the following: (i) phagocytosis to remove cellular debris; (ii) switching from a pro- to anti-inflammatory phenotype in regenerating muscle; (iii) preventing muscle cells from undergoing apoptosis; (iv) releasing factors to promote muscle precursor cell activation and growth; and (v) secretion of cytokines and growth factors to facilitate vascular and muscle fibre repair. These many different roles suggest that a single treatment with one specific target cell population (e.g. neutrophils, macrophages or satellite cells) may not be equally effective in all phases of the post-injury response. To find the optimal targeted, but time-course-dependent, treatments requires substantial further investigations. However, the techniques currently used to induce mechanical injury vary considerably in terms of invasiveness, tools used to induce injury, muscle group selected for injury and contractile status of the muscle, all of which have an influence on the immune and/or cytokine responses. This makes interpretation of the complex responses more difficult. After our review of the literature, we propose that a standardized non-invasive contusion injury is the ideal model for investigations into the immune responses to mechanical skeletal muscle injury. Despite its suitability as a model, the currently available literature with respect to the inflammatory response to injury using contusion models is largely inadequate. Therefore, it may be premature to investigate highly targeted therapies, which may ultimately prove more effective in decreasing athlete recovery time than current therapies that are either not phase-specific, or not administered in a phase-specific fashion.

According to published studies in the US,[1-3] contusion (caused by a blunt, non-penetrating object) and strain injuries account for approximately 90% of all sports-related injuries. Contusions are the most frequent type of injury reported by athletes – up to 60% of all reported injuries in the US. The muscle groups of the arms, hands, legs, feet and buttocks are most commonly affected.[4] Apart from the expected mechanical damage to muscle cells at a microstructural level, skeletal muscle contusion injury involves capillary rupture and infiltrative bleedª 2008 Adis Data Information BV. All rights reserved.

ing, oedema and inflammation. These changes can lead to haematoma formation and can cause compartment syndrome in areas where volume expansion is limited by fascial planes.[5,6] This phenomenon is characterized by severe pain. Due to extensive damage to blood vessels and surrounding tissue, oxygen and nutrients are prevented from reaching nerve and muscle cells,[4,5] thereby exacerbating the already existing tissue damage. Contusion injuries have been clinically documented for a variety of sports in the sportsSports Med 2008; 38 (11)

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related literature, but these reports are largely limited to the relative frequency of contusion injury compared with other types of injury in both contact and non-contact sport, such as rugby,[7,8] soccer,[9] wrestling,[10] hurling,[11] luge[12] and long-distance triathlon.[13] Very few studies have focused on other clinically applicable issues, such as diagnostic criteria. One study did compare the efficacy of different diagnostic methods – these included range-of-motion testing, plasma creatine kinase concentration and ultrasonography. Ultrasound results correlated best with the size of the haematoma (measured in this study as an indicator of severity of injury) and was recommended as the best diagnostic tool available.[14] Symptoms of contusion injuries often do not follow a typical pattern, but generally involve soreness, pain with active or passive motion, limited range of motion, or a combination of these.[6,15] Despite occurrence of these debilitating symptoms, the large variability in the severity of injury complicates both the treatment of and research into this condition to such an extent that a universally accepted, evidence-based treatment modality remains to be developed.[5,16] However, before this can be achieved, a better understanding of the mechanisms and the role of players involved in contusion injury is needed. Interactions between the immune system and skeletal muscle may play a significant role in modulating the course of both the contusion injury and the subsequent muscle repair. As a result of muscle injury and capillary rupture, blood-borne inflammatory cells and cytokines gain direct access to the site of injury.[17-19] The magnitude of the inflammatory response depends on two main factors, namely the severity of injury and the degree of vascularization of the tissue at the time of injury.[19] These factors may be interrelated, with the more severe injury often occurring at sites having a much greater degree of vascularization, leading to a larger inflammatory response. However, this does not discount a role for resident immune cells or non-immune cells’ contributions to the inflammatory response. In addition, although it is generally accepted that cytokines (e.g. tumour ª 2008 Adis Data Information BV. All rights reserved.

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necrosis factor-a [TNFa], interleukin [IL]-1b and IL-6) are integral to the inflammatory response,[20-23] the exact role of each player is still unclear. In the early response to skeletal muscle injury, neutrophils are the most abundant immune cells at the injury site, but within the first 24 hours, neutrophil numbers start to decline and the number of macrophages increases.[18,24] Despite this decline in neutrophil numbers, these neutrophils remain functionally active and their numbers are still elevated from baseline at the site of injury for approximately 5 days, after which their activity gradually returns to preinjury levels. Although the function of neutrophils in response to muscle injury is well described (sections 1.1.2 and 1.1.3), the specific roles played by the macrophages in response to injury in vivo are not equally well understood.[18,25] Studies on muscle injury[18,26,27] and skin wound healing[28,29] are in agreement that limiting the extent of inflammation in the short term, during the ‘neutrophil phase’ of inflammation, could limit the extent of damage, with the benefit of decreasing pain and swelling. In the sportsrelated literature, fibrotic scar formation is associated with slow and incomplete recovery of muscle strength.[30,31] Some studies even suggested that fibrosis after an injury may be the cause of recurrent muscle tears.[32,33] In skin wound healing, excessive scar formation is ascribed to an excessive inflammatory response.[28,29] These investigations may provide scientific support for the beneficial effects of acute anti-inflammatory treatment sought after by athletes. However, depletion of macrophages (i.e. the later phase of inflammation) has long been known to have negative consequences on the healing process, including reduced muscle regeneration, satellite cell differentiation and growth of muscle fibres.[34,35] Using small animal models and in vitro models (e.g. cell culture), it is possible to assess the effects of existing drugs on the different phases of recovery. NSAIDs are commonly prescribed for contusion injury, and many athletes use over-the-counter NSAIDs over long periods of time to reduce Sports Med 2008; 38 (11)

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post-exercise pain and swelling.[36-39] Although short-term NSAID treatment during the early repair phase (1–3 days) may result in a modest inhibition of inflammatory symptoms (swelling and pain), it may in fact have negative effects on the healing of the injured muscle if taken for a longer period (in excess of 3 days).[40-43] These may include promotion of fibrosis[40] and inhibition of both the early[42] and later phases of muscle cell regeneration.[41] A rodent study on muscle reloading (which results in muscle inflammation and necrosis) recently reported decreased necrosis and increased ED2þ macrophage infiltration, which is associated with muscle regeneration and repair, when NSAIDs are administered 8 hours prior to insult, but not when administered 8 and 16 hours after.[44] This result obtained in an animal model warrants further investigation, since it suggests that it may be most effective to use NSAIDs as early as possible. In contrast, steroidal anti-inflammatory agents, such as corticosteroids, have been shown in rodent models to have several adverse effects on healing, such as delaying the clearance of debris at the site of injury and prolonging the muscle regenerative process and recovery of muscle strength, even after only one acute administration.[5,43] Despite the fact that anabolic steroids are inappropriate drugs for athlete use and have detrimental effects on myocardial function,[45] this has not prevented research into possible reasons why athletes abuse drugs in this class. Within the context of attempting to understand how inflammatory responses and muscle healing can be influenced, a rodent study has shown that acute anabolic steroid treatment (the prohibited substance nandralone decanoate in particular) is associated with faster healing and restoration of force development in rodents subjected to experimental contusion injury.[5] In the latter study, steroid treatment was also associated with an initial increase in the inflammatory cell response, suggesting once again that the inflammatory response is a positive force in the healing process. Together, these findings suggest on the one hand that treatment options for athletes are currently far from optimal, and on the other hand ª 2008 Adis Data Information BV. All rights reserved.

Smith et al.

that the different stages to muscle injury and recovery are more complex than previously understood, and that neither can be properly addressed without a greater understanding of the role of the inflammatory response. Both the immune- and muscle-cell responses remain to be fully elucidated, with more detailed attention to the time-course of events, the molecular responses initiated and how these are interrelated, in order for future treatments to target specific processes at specific phases. To achieve this, it is vital to study these phases in a standardized way. The present article therefore aims to elucidate the importance of studying the immune response to skeletal muscle injury by (i) briefly explaining cellular processes known to occur in skeletal muscle after contusion injury, focusing on the early and the late immune cell responses; (ii) discussing important considerations in choosing an appropriate contusion injury model (e.g. invasive vs non-invasive designs); and (iii) providing a review of results reported in studies focusing on immune parameters (rather than parameters of muscle fibre recovery) and specifically using muscle contusion injury models. 1. Responses to Skeletal Muscle Injury The response of skeletal muscle to injury follows a fairly consistent broad pattern, irrespective of the underlying cause of injury, e.g. contusion, strain or laceration. Three distinct phases have been identified (for review see Jarvinen et al.[15]), namely destruction, repair and remodelling. However, due to distinct differences in the mechanisms of injury, the details within these phases are likely to differ to a certain extent. In contusion injury, the ‘destruction phase’ is characterized by the disruption of muscle ultrastructure, as well as extensive damage to the vasculature, which may lead to the formation of a haematoma. Due to this characteristic disruption of the vasculature, the pro-inflammatory immune response is frequently followed by cell death of the damaged muscle fibres. Hurme et al.[46,47] described the time-course of events typically seen after severe contusion injury, induced with a spring-loader hammer. In Sports Med 2008; 38 (11)

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Response relative to maximum

these immunohistochemical and ultrastructural studies, primary damage has been described in terms of the spreading of unchecked necrosis within the preserved basal lamina of injured fibres, for a distance of 1–2 mm. An early mechanism to limit this damage was reported on day 2 after injury: necrotic fibres were ‘closed off’ by the formation of a ‘demarcation band’ – a membrane that demarcated the necrotic part of fibres from non-necrotic parts. Furthermore, in these studies, macrophages were reported to be responsible for mopping up necrotic debris by phagocytosis, phagocytosing necrotic tissue only up to the demarcation membranes. Following the destruction phase, the ‘repair phase’ consists of numerous processes, including phagocytosis of the damaged muscle tissue, regeneration of the striated muscle, production of a connective-tissue scar and capillary revascularization. During the third and final ‘remodelling phase’, the formation of newly regenerated muscle fibres reaches completion and reorganization of the muscle leads to functional repair and a decrease in the size of the lesion. These three phases are usually closely associated and can overlap (see figure 1, adapted from Li et al.[24]), making temporal resolution of the individual phases difficult. For the purpose of this article, the discussion will be limited to two main parts, both relevant to the immune response following injury: the first part will focus on the inflammatory process and possible contribution

Destruction

Repair

Remodelling

100%

7

14 21 Time (days)

28

Fig. 1. Illustrative time-course of regeneration of injured muscle includes three chronologically overlapping, but distinct, physiological events: destruction, repair and remodelling (adapted from Li et al.,[24] with permission). The main timeframe for immune cell involvement (see figure 2 for detail) is indicated by shading.

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of immune cells to secondary damage, while the second will focus on the resolution of muscle injury and the roles of macrophages, cytokines and growth factors in this process. 1.1 Inflammation, Leucocyte Infiltration and Secondary Damage 1.1.1 Vascular Involvement

Following a mild contusion injury, the vasculature in the skeletal muscle is usually not disrupted.[20] Therefore, the arterioles within the injured area can dilate, increasing blood flow to the site of injury. This localized vasodilation may be induced via two mechanisms. One mechanism for vasodilation is via histamine released from mast cells present within the damaged area.[26] A second effect of this localized histamine release is an increase in capillary permeability at the site of injury via enlargement of the capillary endothelial pores. As a result, an increase in the numbers of phagocytic leucocytes and levels of plasma proteins, both crucial to the inflammatory response,[26] are seen in and around the damaged tissue.[48] Another mechanism for vasodilation is the ‘vascular endothelial growth factor – nitric oxide’ (VEGF-NO) pathway.[49,50] VEGF may be secreted by fibroblasts,[51] endothelial cells[52] or monocytes/macrophages[51] in response to hypoxia, oxidative stress, growth factors and cytokines,[53] and activates the nitric oxide and nitric oxide synthase pathways to facilitate vasodilation.[49] Immediately following severe injury, i.e. one in which the vasculature is extensively disrupted, a process of ‘damage control’ is initiated. Platelets adhere to the exposed collagen, become activated as a result and start to release pro-inflammatory mediators such as serotonin (5-HT), histamine and thromboxane A2 (TxA2). Following formation of the platelet plug and the control of haemorrhage, blood-borne immune cells begin to migrate into the area of tissue damage,[15] where they contribute to the localized inflammatory response. 1.1.2 Extravasation

The process of tissue infiltration of circulating, blood-borne neutrophils following injury Sports Med 2008; 38 (11)

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evidence indicates that skeletal muscle cells also express ICAM-1, albeit not proven in the context of muscle injury.[67] Therefore, the possibility exists that neutrophils may be able to migrate through various tissue types, including skeletal muscle, using a mechanism similar to that used for transendothelial migration. Apart from their expression on cell surfaces, ICAM-1 and VCAM1 are also found in soluble forms in plasma. Increased concentrations of soluble adhesion molecules are thought to mediate atherosclerotic inflammation.[68,69] In patients with chronic diseases, exercise training has been shown to decrease levels of soluble ICAM-1.[68] However, in the sports-related literature, no significant change in the concentrations of soluble cell adhesion molecules in plasma was reported after acute exercise bouts.[23,69] Together, these studies suggest that while assessment of soluble cell adhesion molecules are sensitive indicators of the beneficial effects of exercise on systemic inflammation, they may not be useful indicators of the effect of exercise stress on immune function in otherwise healthy individuals. A chronological illustration of white blood cell involvement in the response to skeletal muscle injury is presented in figure 2. Immediately following the injury, neutrophils are the predominant cell infiltrate. Neutrophil infiltration can be detected in the damaged muscle within the first hour following injury. As recently Cell count in muscle relative to cell type-specific maximum response

occurs by rolling, adhesion to and migration through the capillary endothelium.[54] Circulating immune cells roll along the endothelium until interactions between heparin sulphate proteoglycans (HSPGs) expressed on circulating immune cells and endothelium slows them down.[55-57] This is followed by interactions with a variety of cytokines and adhesion molecules,[58,59] which trigger rapid integrin-dependent adhesion to the endothelium.[60] Most circulating immune cells (lymphocytes, monocytes, eosinophils, basophils and natural killer [NK] cells) express the adhesion molecule a4b1 integrin, which facilitates cell adhesion to the activated endothelium by binding to vascular cell adhesion molecule (VCAM)-1.[61,62] However, neutrophils do not express this integrin.[63] Therefore, neutrophils cannot use this to interact with endothelial cells and instead express b2 (CD18) integrins. These integrins facilitate endothelial interaction by binding to immunoglobulin-like proteins (e.g. intercellular cell adhesion molecules [ICAMs]), which are also present on the endothelial cell surface.[64] This pathway requires prior activation of the ICAMs by stimuli such as complement components, cytokines and soluble proteins, e.g. fibrinogen and clotting factor X. A number of recent reviews discuss this process of extravasation in more detail.[60,65] At this early stage, the origin of the cytokines is not known, although the resident macrophages, the endothelial cells, the muscle cells themselves and the circulating immune cells are likely to contribute. The mechanism of neutrophils’ migration once they have entered the extravascular space has not been fully elucidated. Healing of dermal wounds has been extensively studied and the proteins that facilitate neutrophil migration in that context include Mac-1 (CD11b/CD18), which is also a b2 integrin, that was recently shown to facilitate neutrophil migration through monolayers of human synovial and dermal fibroblasts in vitro.[66] In this study, ICAM-1 (expressed by fibroblasts) was only involved in this process in the presence of TNFa and/or interferon-g (IFNg), again indicating the importance of prior activation of ICAM-1. Recent

Neutrophils

Macrophages

T lymphocytes

100%

0

7 Time (days)

14

Fig. 2. Chronological involvement of peripheral immune cells following a contusion injury. Cell counts are represented relative to a typical maximum response. The duration that elevated cell numbers apparent in injured tissues may vary depending on the extent of tissue trauma.

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reviewed by Tidball,[18] neutrophil cell numbers peak approximately 24–48 hours following injury, and can remain elevated for up to 5 days. The dominant behaviour of the neutrophils – relative to other immune cells – is due to the transfer into the blood of large numbers of preformed neutrophils from the bone marrow, and also an increase in production of new neutrophils in the bone marrow, stimulated by the release of chemical mediators from the inflamed region.[18,48,70] These chemical mediators include complement components (e.g. C5), prostaglandins and leukotrienes, as well as factors released by activated platelets (TxA2, 5-HT and histamine).[70] Neutrophils contribute to the post-injury events in two ways: (i) the invading neutrophils have a phagocytic function,[71] clearing the lesion of necrotic debris; and (ii) they magnify the inflammatory process via the release of proinflammatory cytokines such as IL-6 and TNFa (see section 1.2.2).[18,72,73] Although phagocytosis and the neutrophil respiratory burst are important mechanisms in the early phase inflammatory response to muscle injury, they can damage the injured muscle even further, and may result in damage to the healthy surrounding tissue. The processes by which this damage occurs are somewhat controversial (see section 1.1.3). 1.1.3 Secondary Damage

Secondary damage in injured tissue may be the result of a variety of cellular and biochemical processes activated in response to the primary insult. Although the extent of this damage may be related to the severity of the primary damage, it does not seem to be dependent on the type of injury. To date, clear experimental data do not exist to show a direct role for neutrophils in the repair process (for a review, see Tidball[18]). However, neutrophils are the immune cell type that predominates in the injured tissue at the time when secondary damage occurs.[26,46,47] This raises the question of their possible involvement in increasing secondary damage. On the one hand, neutrophils have been shown to generate free radicals during phagocytosis,[74] and neutroª 2008 Adis Data Information BV. All rights reserved.

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phil depletion prior to ischaemia-reperfusion injury was shown to reduce muscle damage by almost 40% in both cardiac[75] and skeletal muscle,[76] providing proof of neutrophil involvement in secondary damage. Similarly, blocking of the neutrophil respiratory burst (using an antiCD11b antibody) is known to reduce myofibre damage.[77] On the other hand, other phagocytic mechanisms may also come into play: lysosomal enzymes, the proteases responsible for digesting phagocytized matter, are usually contained in specialized membrane-enclosed vacuoles. However, it has been proposed that ‘accidental’ release of lysosomes from dead or dying cells into extracellular spaces may occur. Also, lysosomes may release their contents within their own cells, thereby causing necrosis.[19] Lysosomal proteolytic pathways were reported to be responsible for at least 40% of muscle atrophy seen after experimentally induced crush injury, which at first seems to argue against immune cell involvement in secondary damage. However, subsequent experiments indicated that these activated lysosomes were associated with macrophages of a phagocytic phenotype within the areas that contain necrotic fibres,[78,79] while lysosomes in muscle and other uninjured tissue were not activated.[80] A recent paper further showed that macrophages recruited by injured muscle were of a phagocytic, pro-inflammatory phenotype, which later converted to an anti-inflammatory phenotype releasing growth factors.[81] It is therefore clear that macrophages do not contribute to secondary damage, but rather have a role to facilitate recovery (roles for macrophages in facilitating recovery are discussed in more detail in section 1.2.1). From these data, it is clear that there may be multiple contributors to tissue injury. This suggests that a single therapeutic target is unlikely to be sufficient as global treatment for all types and phases of contusion injury. 1.2 Resolution of Muscle Injury

Initiation of injury resolution has previously been defined as the point in time following the injury when the number of neutrophils in the Sports Med 2008; 38 (11)

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region of damage begins to decrease.[15] However, resolution of muscle damage is multi-faceted, and includes many processes involved in three main phases: resolution of inflammation, angiogenesis and the repair of muscle tissue itself. For the purpose of this article, we will focus on the role of the immune system, as well as related cytokine/chemokine systems, in these different events. 1.2.1 Additional Roles for Macrophages

Although phagocytic macrophages appear to play a major role in the removal of cellular debris, it has been proposed that this is not the only role for macrophages following injury.[73,78,79,82] Unlike neutrophils, macrophages may be divided into subtypes with clear differences in cell surface marker expression. These subtypes are commonly labelled according to their occurrence in different tissue types, e.g. ED1þ (most monocytes and macrophages), ED2þ (‘resident’ macrophages mainly seen in tissue) and ED3þ (macrophages usually confined to lymphoid tissue).[79,83-85] After muscle injury, these subtypes appear at the injury site at different timepoints,[73] suggesting multiple functions for macrophages. A further complexity in teasing out the role(s) of macrophages that was briefly mentioned in section 1.1.3, are the recent suggestions and in vitro proof that macrophages can change from one subtype to another, in a manner dependent on their microenvironment. For example, macrophages were reported to express CD163 (ED2) in response to IL-10 and glucocorticoids in vitro.[86,87] These claims were substantiated recently by an in vivo tracer study, which illustrated a switch in macrophage phenotypes in regenerating muscle.[81] Results from co-culture experiments led these authors to conclude that this subtype switch may be triggered by the actual process of phagocytosis,[81] suggesting yet another role for macrophages in recovery. These multiple functions remain to be elucidated, but it is clear that treatments that target all macrophages may inhibit those with potentially beneficial effects. Nevertheless, there is consensus in the literature that in injured muscle, ED2þ and ED3þ ª 2008 Adis Data Information BV. All rights reserved.

macrophages appear later than ED1þ cells.[73,79] Since they are rarely observed in degenerating muscle fibres, these two cell types are not considered to be important role players in the phagocytic process.[79] Although research into their exact contribution to the healing process may still pose more questions than answers, a number of studies reported beneficial roles for these macrophages in both damaged fibres and regenerating muscle.[67,82,88-90] Various models of injury have established at least two mechanisms for cell death in damaged myocytes, namely necrosis and apoptosis.[47,91,92] The occurrence of necrosis as a result of skeletal muscle injury has been well established[46,47,93] and was described in section 1. Although activation of pro-apoptotic signals in skeletal muscle has been reported in failing human cardiac muscle[91] and in skeletal muscle after burn injury,[91] mention of apoptosis in studies describing mechanically injured skeletal muscle is strikingly absent. The reason for the absence of histological evidence for apoptosis may be related to another likely role for macrophages, namely the prevention/limitation of apoptosis.[67,89] For example, satellite cells have been shown to use macrophages as support to promote muscle growth and assist muscle precursor cells to ‘escape’ apoptosis,[67,89] evident to a greater extent in more differentiated myoblasts,[94] via at least four different adhesion molecule systems that are expressed by macrophages in vitro and in vivo.[94] With regard to angiogenesis, it is a well established fact that VEGF is one of the major role players in this process.[50,52,53,95,96] Different sources of VEGF have been identified. For example, differentiating myogenic cells were shown to express VEGF in vitro,[52] which was associated with in vivo neoangiogenesis in muscular dystrophy.[52] Similarly, skeletal myoblasts expressing VEGF were associated with capillary formation after ischaemia/reperfusion injury in rat heart tissue.[96] Recently, CCchemokine receptor 2 (CCR2) knockout mice were reported to show delayed angiogenesis and VEGF production during skeletal muscle regeneration.[97] Since CCR2 is an important Sports Med 2008; 38 (11)

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determinant of monocyte/macrophage recruitment to sites of injury, it is likely that macrophages have an important role in angiogenesis, as suggested by earlier studies.[98-100] Furthermore, a recent study in mice illustrated that macrophages contribute to muscle regeneration by providing both inflammatory and growth-related mediators.[82] Unfortunately, in this particular study, the study design did not allow for subtype-specific investigations. Celltype specific information was reported in an in vitro study that co-cultured macrophages and myoblasts: ED2þ macrophages were shown to be a major contributor to both myoblast proliferation and myotube formation.[101] Furthermore, the latter study also showed that ED2þ macrophage-conditioned culture media had similar effects on myoblasts to the macrophages themselves. These results suggest that this subtype of macrophages may serve as a major source of growth factors and cytokines that promote healing.

1.2.2 Inflammatory Cytokine and Growth Factor Involvement

Pro-inflammatory cytokines can be secreted locally in injured muscle by a variety of cell types, including neutrophils, activated macrophages, fibroblasts, endothelial cells and damaged muscle cells (for a detailed review see Cannon and St Pierre[73]). Each of these cell types may well be operating in different time-frames depending on the time-course of their recruitment to the injured area. This complex inflammatory response develops rapidly and only ceases more than a week later (approximately 10–14 days) when the injured area is properly cleared of all damaged tissue.[72,73] The relative contribution of the various cell types present in muscle to this process is unclear and complex to study, since most cytokines originate from more than one cell type and their functions involve several interrelated steps. One way of elucidating cell type- or cytokinespecific roles would be to inhibit the function of either a specific cell type or a specific cytokine, using antibodies or knockout animals. The eliminated factor may play an independent role or a ª 2008 Adis Data Information BV. All rights reserved.

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role in recruitment or activation of another factor. The absence of the eliminated factor may also, in the long-term, lead to compensation by upregulation of other cell types or cytokines. Therefore, such models are complex to interpret. Another state-of-the-art technique (cDNA microarray) allows for investigation into changes in gene expression of inflammatory mediators following muscle injury.[102,103] Although these studies have an important place in science, gene expression does not always correlate with protein expression (i.e. actual production of the inflammatory mediator). Another, less drastic way may be to consider the chronology of cell availability within the damaged area, together with the role of different factors secreted by these cells, to give an indication of the importance of specific cell types to the various phases of the inflammatory process. For example, neutrophils are generally accepted to play a major role in the early inflammatory response to contusion injury, and have been shown to play a role in the recruitment of circulating macrophages to the site of injury, via secretion of chemotactic factors (e.g. IL-1, IL-8).[15,24] However, the increase in macrophage numbers seen in damaged muscle tissue at approximately 2 days postinjury, coincides with the decline in neutrophil numbers.[18] This may on the one hand suggest that macrophages can play a role in sustaining the inflammatory response initiated by damaged cells and neutrophils, at a time when both damaged cell tissue and spent neutrophils are cleared from the injury site. On the other hand, the micro-environment may have changed dramatically in terms of availability of growth factors, etc. by the time of peak macrophage involvement. Therefore, factors secreted by macrophages may have a different net effect compared with similar factors when secreted by neutrophils due to differences in the availability of enhancing or inhibiting factors. Proof of such interactions may be deducted from the information in table II, where the same cytokine (e.g. IL-6) is suggested to have opposing functions at different times during the response to injury. Tables I and II summarize the chronology of major cell types present in injured muscle, the Sports Med 2008; 38 (11)

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Table I. Involvement of the main cell types responding at different stages following contusion injury, with their main secretory products Cell type

Cytokine/growth factor secreted in different stages of muscle repair destruction of muscle fibres

Damaged muscle fibres

inflammation

regeneration

TNFa

TNFa

IL-1b

IL-1b

IL-1b

MCP-1

IL-6

IL-6

FGF-2

MIP-1a MCP-1

Endothelial cells

Fibroblasts

IL-1a

IL-1b

IGF-1

IL-1b

IL-6

HGF

IL-6

IL-8

FGF

G-CSF

PDGF

M-CSF

VEGF

IL-1a

IL-6 IL-8 G-CSF M-CSF VEGF

Neutrophils

TNFa

TNFa

IL-1b

IL-1b

IL-1b

TGF-b

IL-8 NK cells

IL-1a

IFNg

IFNg TNFb

ED2þ macrophages

TNFa

TGF-b

IL-6

IL-1b

VEGF

IL-15 FGF-2 IGF-1 LIF

T lymphocytes

IFNg TNFb IL-1b IL-2 IL-6 TGF-b MIF

B lymphocytes

TGF-b IL-2 IL-6 Continued next page

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Table I. Contd Cell type

Cytokine/growth factor secreted in different stages of muscle repair destruction of muscle fibres

Muscle precursor cells/myotubes/ regenerating fibres

inflammation

regeneration

IL-1b

IL-1b

IL-6

IL-6 LIF IGF-1, IGF-2 FGF-1, FGF-2 TGF-b HGF MIF HMGP CNTF

CNTF = ciliary neurotrophic factor; ED2+ = ‘resident’ macrophages mainly seen in tissue; FGF = fibroblast growth factor; G-CSF = granulocyte colony stimulating factor; HGF = hepatocyte growth factor; HMGP = high-mobility group proteins; IFN = interferon; IGF = insulin-like growth factor; IL = interleukin; LIF = leukaemia inhibitory factor; MCP = monocyte chemotactic protein; M-CSF = macrophage colony stimulating factor; MIF = macrophage migration inhibitory factor; MIP = macrophage inflammatory protein; NK = natural killer; PDGF = platelet-derived growth factor; TGF = transforming growth factor; TNF = tumour necrosis factor; VEGF = vascular endothelial growth factor.

different inflammatory cytokines and growth factors produced by these cells and their possible involvement in post-injury events. Taken together, these findings suggest that besides their role in phagocytosis, immune cells such as macrophages and neutrophils play pivotal roles in mediating muscle repair, either directly by secretion of growth factors, or indirectly by recruitment of other cell types. 2. Injury Models – Technical Considerations Several confounding factors complicate research on muscle injuries and influence our ability to further elucidate the exact roles of immune cells, particularly macrophages, in damaged tissue. These include inter-individual variations in the severity of injuries that occur in humans, as well as the invasive nature of methods for inflicting injury in some models and methods used for obtaining muscle samples for analysis. In this section, animal models of muscle injury (invasive and non-invasive) will be described. Particular emphasis will be placed on the relevant technical considerations that may influence reª 2008 Adis Data Information BV. All rights reserved.

sults obtained, variability between the different models and the suitability of each for inflammation-related research, all of which contribute to the complexity of studying the immune response to muscle injury. 2.1 Invasiveness of Injury Model

Skeletal muscle contusion injury is a proven result of various methods of inducing mechanical injury in animal models.[20,90,138] The model most commonly described in the literature makes use of a single impact trauma to the muscle, either with or without prior surgical exposure of a selected muscle group.[20,88,90,138-140] For example, the mass-drop injury model introduced by Kvist and colleagues,[141] and also later described by Stratton et al.[142] involves dropping a solid weight with a flat impact surface (varying in diameter and mass) from various heights onto the specific muscle (see figure 3 for a representative illustration). Both localized and systemic inflammation have been studied using the invasive version of this model.[20] Although changes in skeletal muscle expression of the different cytokines (IL-1b, IL-6 and TNFa) were reported, the Sports Med 2008; 38 (11)

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Table II. Cytokines and growth factors secreted in response to contusion injury with their possible roles in the recovery of muscle, nerve and capillary tissue Cytokine/growth factor

Injury-related functions

References

TNFa

Activates proteolysis in the presence of cortisol

104

Upregulates ICAM-1 and VCAM-1 expression, to facilitate immune cell infiltration

73

Upregulates IL-1b secretion

105

Upregulates IL-6 secretion by myoblasts

21

IL-1a

Activates proteolysis independent of cortisol

106

IL-1b

Role to increase protein turnover by inhibition of IGF-1 secretion

74,107

Upregulates ICAM-1 and VCAM-1 expression, to facilitate immune cell infiltration

73

Activates endothelial cells to secrete G-CSF and GM-CSF

108

Upregulates IL-6 production and MCP-1 expression

17,21,24

Inhibits satellite cell differentiation to enhance proliferation

109

Upregulates hypothalamo-pituitary-adrenal axis to increase cortisol levels

110

IL-6

Suggested role in rupture of injured myofibres

111

Upregulates IL-1b secretion

105

Downregulates TNFa secretion

112,113

Downregulates concentrations of MIP-2, GM-CSF and IFNg

113

Suppresses effect of IGF, resulting in loss of myofibrillar protein

112

Autocrine secretion by myoblasts associated with increased myoblast proliferation

101

MIP-1a

Recruitment of circulating monocytes into injured tissue

114

MCP-1

Recruitment and activation of macrophages

115,116

Role in functional restoration of muscle after injury

117

IL-8

Decreases neutrophil infiltration via inhibition of its adhesion to endothelial wall

118

Upregulates monocyte infiltration into injured tissue

24

G-CSF

Promotes granulocyte production in bone marrow

108

M-CSF IFNg

Decreases satellite cell apoptosis and promotes its proliferation

119

Promotes monocyte/macrophage production in bone marrow

108

Acitvates ICAM-1 to facilitate neutrophil migration from circulation to site of injury

66

Associated with trauma-induced muscle wasting

120

Stimulate myoblast proliferation

121

FGF-1, FGF-2

Enhances myoblast proliferation by inhibition of differentiation via inhibition of MyoD expression

109,122,123

IGF-1, IGF-2

Enhances myoblast differentiation by increasing myogenin expression

124

Stimulates myosin heavy chain production

125

HGF

Enhances myoblast proliferation by inhibition of differentiation via inhibition of MyoD expression, and increases myoblast migration into injured tissue

52,122

PDGF

Enhances myoblast proliferation by inhibition of differentiation via inhibition of MyoD expression, and increases myoblast migration into injured tissue

52,122

VEGF

Facilitates vasodilation in response to ischaemia

50,126

Promotes angiogenesis after injury

96,97

Role in angiogenesis at sites of inflammation

127

Provide chemotactic signal to recruit muscle progenitor cells from bone marrow

128

SDF-1

Continued next page

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Table II. Contd Cytokine/growth factor

Injury-related functions

References

TGF-b

Stimulates scar formation

68,129

Enhances angiogenesis

68

IL-15

Induces myosin heavy chain synthesis, and accelerates process in presence of IGF-1

73

LIF

Suggested function in recovery of intramuscular motor nerves

130,131

IL-2 MIF

Induces satellite cell proliferation via activation of the JAK2-STAT3 signalling pathway

132

Stimulates fibroblast proliferation

133

Stimulates fibroblast proliferation

133

Associated with specialization of tissue and inhibition of macrophage infiltration

134

TNFb

Stimulates fibroblast proliferation

133

HMGP

Maintenance of muscle precursor cell’s state of differentiation, with expression decreasing as differentiation progresses

135,136

CNTF

Regeneration of motor neurons in muscle

137

CNTF = ciliary neurotrophic factor; FGF = fibroblast growth factor; G-CSF = granulocyte colony stimulating factor; GM-CSF = granulocytemacrophage colony-stimulating factor; HGF = hepatocyte growth factor; HMGP = high-mobility group proteins; ICAM = intercellular cell adhesion molecules; IFN = interferon; IGF = insulin-like growth factor; IL = interleukin; LIF = leukaemia inhibitory factor; MCP = monocyte chemotactic protein; M-CSF = macrophage colony stimulating factor; MIF = macrophage migration inhibitory factor; MIP = macrophage inflammatory protein; MyoD = myogenic regulating factor (related to fusion and terminal differentiation of muscle cells); PDGF = plateletderived growth factor; SDF-1 = stromal cell-derived factor 1 (also known as CXCL12); JAK2-STAT3 = janus-activated kinase 2 signal transducer and activator transcription 3 protein; TGF = transforming growth factor; TNF = tumour necrosis factor; VCAM = vascular cell adhesion molecule; VEGF = vascular endothelial growth factor.

lack of sham-operated groups resulted in failure to account for cytokines released as a result of the surgical procedure itself. Surgical (sham) procedures involving damage to the skin have been used in other areas of research as control, and have been reported to increase circulating cytokine levels, in particular those of TNFa and IL-6, within the first few hours post-surgery.[143] Considering that the inflammatory response to contusion injury is also launched during this same time period, such a confounder could affect results obtained. Therefore, in particular when studying interactions between the immune system and muscle, a non-invasive model of injury is imperative. One variation of this model uses the placement of a heavier weight on the muscle without impact force (i.e. no impact damage), but for a prolonged period of time, usually two or more hours.[144,145] Apart from this model resulting in more severe damage due to longer-term occlusion of blood flow, it more closely simulates muscle injury incurred in accidents where the ª 2008 Adis Data Information BV. All rights reserved.

subject is trapped, and is therefore not ideally suited for studying sports-related injuries.[146] Forceps crush injury is another invasive model of contusion injury. Prior to the injury, the muscle is surgically exposed (as with invasive mass-drop), placed in between the jaws of a forceps and then bruising is achieved by pinching the forceps manually or by dropping a weight onto the forceps. Apart from the invasiveness of this method, manual contusion injury is difficult to deliver reproducibly. Despite these complications, this model has been used, with success, to study secondary damage,[147] as well as skeletal muscle regeneration[139,140,148] and possible interventions.[147] However, the inflammatory response has not been investigated. 2.2 Details of Drop-Mass Weight

Murine and rat models have been used to study contusion injury. Given the difference in body size between mice and rats, it is not unexpected that the mass of drop-weights and Sports Med 2008; 38 (11)

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Weight

compared with the periphery. The infiltration of immune cells into the site of injury was reported to be more concentrated to the middle of the injury when a spherical impactor tip was used than with a flat surface.[5,152,155] The diameter of the weight’s impact surface will also influence the impact area and has varied from study to study. If a weight with a larger impact surface hits the muscle belly, the injured area will be wider than when a mass with a smaller impact surface is used. In summary, the characteristics of shape and diameter of the impact surface will both ultimately influence the pattern of injury and the subsequent infiltration of the immune cells. Therefore, in a discussion of existing literature and in future studies, care should be taken to describe the method of injury induction comprehensively. Also, the choices made with regard to the injury induction method will influence the outcome and should be selected (and verified) based on the desired injury to be simulated. 2.3 Selection of Muscle Group

Fig. 3. Representative illustration of a non-invasive, standardized ‘drop-mass injury jig’.

hence the impact force used to induce injury also differed. Two specific approaches previously used in rats to induce contusion injury with the mass-drop technique were either relatively heavy weights from a relatively small height (640 and 700 g from 27 and 25 cm, respectively),[142,149-151] or a smaller weight, but from a greater height (171 g from 102 cm).[1,152-154] Similarly, injuries to mice were also typically induced using one of these strategies.[20,88,155] However, other factors in addition to the size of the weight and the drop height also influence the injury produced, for example the shape of the weight. The impact surface influences both the size of the impact area and severity of the skeletal muscle injury. When a weight with a flat impact surface is used, an injury of uniform severity is achieved, but if a weight with a spherical impact surface is used, the injury induced is more severe in the middle of the impact area ª 2008 Adis Data Information BV. All rights reserved.

Due to the different metabolic phenotypes seen in different muscle fibres types, the degree of vascularization differs between fibre types. Type I fibres have a high demand for oxygen and show a high degree of vascularization, which provides a rich source of oxygen and nutrients to the fibres. In contrast, type IIb fibres are oxygen independent, with a reduced capillary supply when compared with type I fibres.[156] Although whole muscles most frequently contain a mixture of different fibre types, the proportions in which they are found differ substantially between different muscles and can also differ between different species or individuals within a specific species.[157] To date, the majority of research on skeletal muscle crush injury has made use of the gastrocnemius muscle,[1,5,149-151,153,154,158,159] or the tibialis anterior muscle.[88,140,145,148] Both of these muscles possess type II fibres, but only the gastrocnemius muscle is a mixed muscle, also containing type I fibres.[160] In addition, the gastrocnemius muscle is relatively large, which makes it possible to injure the muscle without Sports Med 2008; 38 (11)

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bone involvement, which on the one hand is less painful and therefore more ethically acceptable, and on the other making it less likely that the molecular response is complicated by factors released from injured bone or periosteum. The belly-shaped/fusiform nature of gastrocnemius muscle is similar to that of the biceps muscle, which frequently receives contusion injuries in games such as rugby. Therefore, in our opinion, the gastrocnemius muscle is a good candidate to use when studying sportsrelated contusion injuries. Similarly, for investigation of other sports-related injuries, care should be taken when interpreting results obtained in muscle groups not directly relevant to the sport being studied. With regard to the immune and cytokine system, it has been shown that muscle fibres secrete cytokines in a fibre-type specific manner. For example, in the triceps, vastus and soleus muscles of humans at rest, TNFa and IL-18 were expressed in type II fibres only, while IL-6 expression was more prominent in type I than in type II.[161] It is presently unclear how the fibre types differ during the phases of muscle destruction, repair and remodelling. 2.4 Contractile Status of the Muscle

The contractile status of the muscle at the time of injury has been shown to influence the muscle’s susceptibility to injury. In one study, muscle was shown to be less susceptible to injury when in the maximally contracted state.[152] However, the extent of muscle relaxation was also a factor. Muscles were only fully relaxed after general anaesthesia, highlighting the importance of similar protocols for animal treatment during such experiments. In sportspersons, injuries occur during practices or competition and will therefore be accompanied by prior exercise and, if not severe, also by subsequent exercise. Exercise, and more specifically contracting muscle, has been shown to contribute to the production of some proinflammatory cytokines, such as IL-6.[162,163] However, muscle production of IL-1b and TNFa ª 2008 Adis Data Information BV. All rights reserved.

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appears to be independent of contraction.[164-167] Cytokines produced within contracting skeletal muscle cells and released into the circulation, will bring about further downstream cytokinemediated events, possibly influencing the systems under investigation. However, it is not clear what volumes or intensities of exercise may exacerbate the destruction phase, either delay or promote the repair phase or enhance the remodelling phase. This makes it difficult to provide evidence-based guidelines for athletes’ recovery. Given the above-mentioned considerations regarding muscle injury, ‘clean’ models currently used to investigate the effect of the immune response to muscle injuries, such as contusion injury models, remain somewhat disappointing. Despite this lack of an ‘ideal’ model, we will briefly discuss the literature focusing on immunerelated investigations using contusion injury models. 3. Immune-Related Studies Using Contusion Models 3.1 Cytokine Focus

Unlike the many studies investigating cytokine and immune responses to stretch-induced injury, studies concerning contusion injury are relatively scarce. Those investigating the immune response following a contusion injury are mostly limited to studying selected cytokines. Nevertheless, the mass-drop injury model in rats has been used by more than one research group to observe acute (hours to a few days) histological changes in the muscle directly after injury and during the recovery phase.[1,149] Parameters that have been investigated include: extent of inflammatory infiltration, the degree of vascular and muscle tissue disruption, collagen formation and tissue re-organization to name but a few. However, these acute observations were limited to the use of light microscopy, with identification of cell types and tissues involved facilitated by using basic stains (uranyl acetate and lead citrate). Changes in muscle strength and biomechanics of the injured muscle Sports Med 2008; 38 (11)

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were also reported. However, specific investigations with regard to mediators of inflammation or resolution thereof were not included in these studies. To date, only three papers reported on the involvement of cytokines in muscle injury in a mass-drop contusion injury model by actual measurement of cytokine concentrations or gene expression.[20,151,168] One paper reported transient increases in IL-1b, and TNFa in an invasive mass-drop injury model, with peak concentrations in muscle seen on day 4 postinjury in the group exposed to a mild contusion injury (100 g weight dropped from 130 mm). In the group exposed to a severe contusion injury (200 g weight dropped from 130 mm), IL-1b and TNFa levels rose more gradually, and continued to increase up to day 8 post-injury. IL-6 levels remained unchanged at all timepoints with mild injury, but were relatively high on day 2 post-injury, decreased on day 4 and then increased again on day 8 after severe injury.[20] Unfortunately, no statistical analysis was performed to compare timepoints, so it is not clear whether these changes were significant. Nonetheless, a second study also points indirectly towards a possibly important role for IL-6 and IL-6-related cytokines in regeneration.[151] In a similar mass-drop injury model, the signal transducer and activator transcription 3 protein (STAT3) was exclusively induced in the activated satellite cells, proliferating myoblasts, and surviving myofibres in the regenerating muscle. STAT3 is associated with the leukaemia inhibitory factor (LIF)-signalling molecule, which is an IL-6 super family member, and LIF has been shown previously to play a role in muscle regeneration using other injury models.[130,169] The third study did not investigate inflammatory cytokines, but rather focused on the inhibitory effect of therapeutic ultrasound on mechano-growth factor expression after injury, suggesting a possible decreased capacity for regeneration.[168] These findings echo the conclusion of an earlier paper, which suggested that pulsed ultrasound therapy may promote the initial satellite cell proliferation phase, but ª 2008 Adis Data Information BV. All rights reserved.

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found no significant beneficial effect on overall morphological aspects of muscle regeneration and revascularization.[170] The role(s) of the cytokines are much more complex than what is presented in these limited studies, as reflected by the detail in tables I and II, and may act both upstream and downstream of proteolysis, thus playing roles in both the destruction and repair phases.[73] 3.2 Other Possible Treatment Options Investigated

Additional information regarding the inflammatory response after injury could possibly be extrapolated from investigations on the efficacy of various NSAIDs on muscle regeneration following contusion injury, although most of these papers did not include direct assessment of inflammatory parameters.[43,140,159] For example, two studies of rat contusion injury reported no negative effect of five different types of NSAID treatment on long-term muscle regeneration,[140,159] except at lethal doses.[140] A third paper reached the same conclusion with regard to muscle regeneration, but did report decreased neutrophil and macrophage infiltration earlier in the recovery phase (day 2 postinjury) and slower resolution of inflammation in response to 5 days of NSAID treatment.[171] More direct evidence of immune involvement was reported in an animal model of contusion injury, where cyclo-oxygenase-2 (COX-2) inhibition by NSAID infusion were shown to result in faster restoration of microcirculation disrupted as a result of a mass-drop injury, thereby reducing skeletal muscle secondary tissue damage – measured in this study as leucocyte rolling and adhesion to the vascular endothelium.[90] Although this seems to prove a positive effect of NSAIDs immediately after injury, other studies suggest that total inhibition of the inflammatory phase does not benefit the capacity for regeneration. For example, a study using myogenic precursor cells isolated from COX-2 knockout mice, reported a decreased capacity for fusion of these cells in culture.[41] This result is supported by an in vivo Sports Med 2008; 38 (11)

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study, albeit using a model of freeze injury, which reported decreased myofibre regeneration after long-term treatment with another COX-2 inhibitor.[42] In our opinion, the literature with regard to NSAID treatment therefore holds enough proof that an NSAID does not have a negative effect on muscle recovery from injury if its use is limited to 3 days post-injury, but that longer-term treatment has definite detrimental effects on speed of recovery. Another possible treatment option with few adverse effects may be cryotherapy. MenthChiari et al.[172] investigated the relationship between secondary muscle damage after massdrop contusion injury and the interactions between leucocytes and endothelial cells, essential in the secondary inflammatory response. Five hours following contusion injury, the injured group had a significantly higher number of rolling and adherent neutrophils than the sham group.[172] Using similar visualization and injury methods, cryotherapy after contusion injury was reported to result in decreased numbers of rolling and adhering leucocytes.[173] In addition, although no direct evidence exists to prove that granulocytes contribute to secondary damage (as discussed in section 1.1.3), a number of studies illustrated direct associations between neutrophil infiltration and secondary muscle damage. For example, local superficial cryotherapy was reported to decrease endothelial dysfunction, resulting in decreased granulocyte infiltration, which was linked to a decrease in myofibre membrane disruption (using desmin staining).[93,174] This study illustrates that the role of neutrophils may be an important determinant of the extent of damage, and warrants further investigation. An additional mechanism for the efficacy of cryotherapy in limiting secondary damage has also been suggested: 5 hours of ice therapy was reported to inhibit the extent of loss of oxidative function (assessed by triphenyltetrazolium chloride reduction) in crush-injured tissue.[147] Therefore, cryotherapy should be further investigated in models of sport-related injuries, as a possible complimentary treatment to at least prevent secondary damage. ª 2008 Adis Data Information BV. All rights reserved.

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3.3 Contusion Injury: the Ideal Model for Injury Research?

Taken together, the results of the studies discussed (in section 3) show that the inflammatory response seen after contusion injury is in many ways similar to those reported after other types of skeletal muscle injury, e.g. stretch injury[77] or laceration,[175] but with the added benefit of having no skin or tendon involvement. Also, a contusion model allows investigation of events following damage to both muscle and vascular tissue, which is not common in other injury models. This illustrates that it is an appropriate model for studying immune-related events occurring after muscle injuries, with the added benefit that it can be standardized easily in vivo. It is clear that research into the inflammatory responses during muscle repair after contusion injury is limited. Also, due to the very specific aims of these investigations, and the invasive nature of exposing the muscle prior to contusion in some of these studies, which may lead to additional secretion of cytokines by these damaged muscle fibres,[15,130] literature on integrated responses of the cytokine and immune systems is lacking. Although models of other types of injury exist to investigate this topic, these models are not without complications. For example, although a standardized model of in vivo stretch injury was recently described in rabbits,[77] this – and other – in vivo stretch injury models cannot exclude the involvement of tendons in the response to injury. On the one hand, differences in tendon properties (such as compliance) may increase the variability in the extent of muscle injury induced. On the other hand, injury to the tendons themselves may add to the complexity of the results. Similarly, in vivo laceration injury will necessarily involve injury to the skin as well, and since keratinocytes are known to secrete several pro-inflammatory cytokines,[176] this model is also open to added complexity. Characterizing a simple in vivo model that yields reproducible injuries at different levels of severity is therefore essential to enable research into the interaction of the immune Sports Med 2008; 38 (11)

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and muscle systems. Furthermore, such a model may assist in determining more clearly the effects of current treatments on the destruction, repair and remodelling phases associated with muscle injury, which could lead to the development of better treatment modalities.

4. Conclusions Muscle contusion injuries, common in contact sport, have been studied in animal models, and recently particular attention has been paid to skeletal muscle regeneration after injury. Attention has also been focused on various treatment modalities in order to speed up the recovery process as well as to facilitate antiinflammatory actions. Although it is known that the immune system plays a major role in skeletal muscle regeneration after injury,[18,43,81,89] little detailed research has been done on the immune components of the physiological response to mechanical muscle injuries, so that some conclusions are currently quite generalized or even conflicting. This makes it difficult to provide incontrovertible evidence-based recommendations for treatment. Current treatment modalities may address some, but not all, of the intended benefits because of the complexity and phasic nature of both the injury progression and the healing process. This review clearly highlights some of the complexities of the injury response, secondary damage, regeneration and repair. The subsequent remodelling events have not been addressed. We conclude that a single treatment is unlikely to optimally improve healing, but rather targeted treatments, administered in a time-dependent manner, need to be developed. To achieve this, the specific roles of the different cytokines and growth factors, as well as the involvement of the various immune cells in the different phases of muscle injury, remain to be properly elucidated. This article has also pointed out that certain aspects of the different muscle contusion injury models need to be considered in order to promote a reproducible model of muscle contusion injury. We further suggest that future investigations using injury models, should specifically quantify ª 2008 Adis Data Information BV. All rights reserved.

and report the degree and severity of muscle injury achieved, in order to facilitate interpretation of results and placement of conclusions into context with other research. It is only when these factors are controlled that a physiologically relevant model can be established with which new or existing treatments can be tested, which will further improve our evidence base, particularly for the less-well investigated local immune response to contusion injury. Acknowledgements No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review. No other persons beside the authors contributed to this review.

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Correspondence: Dr Carine Smith, Department of Physiological Sciences, Stellenbosch University, Private Bag X1, Matieland, 7602, South Africa. E-mail: [email protected]

Sports Med 2008; 38 (11)