Journal of Orthopaedic & Sports Physical Therapy

Official Publication of the Orthopaedic and Sports Physical Therapy Sections of the American Physical Therapy Association
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What Mechanisms Contribute to the Strength Loss That Occurs During and in the Recovery from Skeletal Muscle Injury?
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Christopher P. Ingalls, PhD2 Shipping/Billing PhD3 Dawn A. Lowe, Information R. B. Armstrong, PhD4 Name _______________________________________________________________________________________________
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tractions.15,19 The strength loss City In the workplace or on the athletic field, muscle strength can be decreased by 50% or more _______________________________State/Province __________________Zip/Postal Code _____________________ following performance of a relatively few high-force, eccentric contractions. The strength loss can associated with an acute bout of be prolonged, taking a month or more for complete recovery. It is important to understand the eccentric contractions can exceed Phone _____________________________Fax____________________________Email _____________________________ cause(s) of the strength loss so we can develop means of preventing or attenuating this loss. The 4050% in both human and anicellular-level mechanisms explaining email of strength following contraction-inducedI Yes muscle Would you like to receive JOSPT the loss updates and renewal notices? I mal models.9,14,21 Figure 1 illusNo injury remain controversial. The traditional thought is that initial strength loss is due solely to trates for our mouse model how damage to force-bearing structures within the muscle, as evidenced by histopathology. In addition, rapid and marked the strength inflammation in the days following injury is commonly thought to exacerbate the strength loss. We loss can be. Probably even more Payment Information Recent data show that most of the early strength loss results from a present data to the contrary. important than the magnitude of failure of excitation-contraction coupling processes and that a slow loss of contractile protein in I Check enclosed (made payable to the JOSPT). the strength loss is how slow the the days following injury prolongs the time for recovery. J Orthop Sports Phys Ther recovery can be. The time re2002;32:5864. I Credit Card (circle one) MasterCard VISA American Express quired for complete recovery of Key Words: calcium, eccentric, excitation-contraction coupling, strength strength can be more than one Card Number ___________________________________Expiration Date _________________________________________ month for both animals and humans (Figure 2).9,11,18 Signature ______________________________________Date __________________________________________________ Because the strength loss can hough traumatic skeletal muscle injuries (eg, crush, lacerahave a long-lasting impact on pertion) can have a dramatic impact on function, they occur formance in the workplace, on the relatively infrequently.To orderother hand, email or mail to: athletic field, and in the home, it On the call, fax, contraction1111 North Fairfax Street, Suite 100, work or induced muscle injury resulting from strenuousAlexandria, VA 22314-1436 is important to understand the exercise Phone 877-766-3450in Fax 703-836-2210 Email: subscriptions@jospt.org strength loss so occurs frequently our daily lives and can have a cause(s) of the marked and prolonged effect on our functional capacity. The injury is that we can develop means of preassociated with the performance of eccentric contractions, which are Thank you for subscribing! venting or attenuating the loss. also known as eccentric muscle actions or as lengthening or plyometric The objective of this commentary contractions. During an eccentric contraction, the muscle lengthens is to discuss the cellular-level while it is active. Force production during this type of contraction can mechanisms responsible for the exceed that produced during isometric or concentric contractions by as strength loss following contractionmuch as 80100%. The high forces that are generated are generally induced injury. We have defined thought to be responsible for the injury associated with eccentric conthree broad categories into which all mechanisms potentially contributing to the strength loss can be partitioned. The three categories 1 Associate professor, Department of Physical Therapy, Georgia State University, Atlanta, GA. 2 include mechanisms that result in Assistant professor, Department of Kinesiology & Health, Georgia State University, Atlanta, GA. 3 Postdoctoral fellow, Department of Biochemistry, Molecular Biology, and Biophysics, University of (1) damage to force-generating or Minnesota, Minneapolis, MN. 4 Department chair, Department of Health and Kinesiology, Texas A&M University, College Station, TX. force-transmitting structures, or Send correspondence to Gordon L. Warren, Department of Physical Therapy, Georgia State University, both, (2) a failure to activate inAtlanta, GA 30303-3083. E-mail: phtglw@langate.gsu.edu tact force-generating structures,

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Journal of Orthopaedic & Sports Physical Therapy

FIGURE 1. Peak torque production during two 150-contraction protocols. Data are from Warren et al21 and were acquired using our model for inducing injury to the anterior crural muscles of intact, anesthetized mice. One group of mice performed 150 maximal eccentric contractions (open circles) and a second group performed 150 maximal concentric contractions (filled circles). There were 12 seconds between the 120-ms long contractions so each protocol lasted 30 minutes. Note that the initial peak eccentric torque was approximately twice that observed for the concentric protocol. The strength loss for the eccentric contraction protocol was rapid, practically complete by 10 minutes (ie, 50 contractions) into the protocol.

structures to indicate both force-generating and force-transmitting structures. In this perspective, we discuss the three categories of mechanisms and their relative contributions to the strength loss during and in the recovery from the injury. The traditional thought on the cause of the strength loss is that the initial decrement is due solely to damage of the force-generating or forcetransmitting structures, or both, within the muscle. Inflammatory processes occurring in the days after injury are assumed to result in a degradation of force-bearing structures that causes a secondary loss of strength. However, we contend that the data accumulated over the last decade indicate a different etiology. These data indicate that most of the initial strength loss is due to a failure to activate intact force-generating structures and that in the days following injury, there is no secondary loss of strength. Most of the data discussed in this perspective were derived from animal models of contraction-induced muscle injury and, in particular, models employing rodent muscles or muscle fibers performing maximal eccentric contractions during electrical stimulation. Therefore, one must be cautious in generalizing these findings to humans in which the strength loss results from performance of maximal or submaximal voluntary contractions.

CLINICAL COMMENTARY

Damage to Force-Generating or Force-Transmitting Structures, or Both

Damage to force-bearing structures, either those internal or external to the muscle fibers, has generally been assumed to account for most if not all of the strength loss following eccentric contractions. Because histopathological damage, which is considered by many to be the gold standard marker of muscle injury, is apparent following performance of injurious eccentric contractions, the histopathology has been presumed to explain the strength loss. However, the link between the histopathology and strength loss is not strong, either temporally or quantitatively. The greatest strength deficit occurs immediately after an injurious bout of exercise,4,12,14,21 but histopathology at the light microscopic level is not apparent in muscle cross-sections until two to four days later when inflammatory cells have invaded the tissue.1,14,16 A quantitative dissociation of the strength loss from histopathology is a common observation in the literature. Immediately following a bout of eccentric contraction-biased exercise performed by rats, lesions were observed in longitudinal sections cut from the injured soleus muscles.17 The lesions, primarily A-band lesions, constituted 0.35% of the muscle volume. The strength loss was not quantified in this particular study by Ogilvie and colleagues,17 but a few years later, the same laboratory using the same
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FIGURE 2. Long-term strength changes following an injurious bout of eccentric contractions done by the elbow flexors of human subjects. Data are from Howell et al.9 The subjects did three sets of 515 eccentric contractions per set. The half-time for strength recovery was estimated to be five to six weeks.

and (3) a frank loss of force-generating or forcetransmitting structures, or both. We define forcegenerating structures as actin, myosin including the cross-bridge, and the associated contractile regulatory proteins. Force-transmitting structures are defined as the passive force-bearing structures in series with force-generating structures (eg, z-line, aponeurosis, tendon). In addition, we use the term force-bearing
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injury protocol reported maximal isometric strength to be reduced by 20%.24 Thus, on a percentage basis, the strength loss was 57-fold greater than the histological damage. Similar observations were made by Lowe and colleagues14 as they reported for mouse muscles exhibiting a 50% strength loss, no more than 5% of the fibers in cross-section showed histopathology at any time in the first two weeks following injury. In addition, McCully and Faulkner15 reported for three groups of injured mouse muscles exhibiting strength losses of 38, 60, and 84% that histological damage was evident in only 5, 21, and 34% of the muscle cross-sectional area, respectively. Because muscle strength is normally directly proportional to viable muscle cross-sectional area, the observed strength loss was 2.5- to 7.6-fold greater than what one would have predicted from the histopathology. The dissociation of strength loss and histopathology extends in the other direction as well (ie, greater histopathology relative to the magnitude of the strength loss). Gibala and collegues7 observed that when human subjects did an injurious bout of eccentric contractions using their elbow flexors, 80% of the fibers showed signs of damage both immediately and two days after injury. However, maximal voluntary isometric strength was only decreased by 32 39% at these times. Similarly, Hortobagyi and col leagues8 reported for their subjects that 23% of the area in vastus lateralis muscle longitudinal sections exhibited histopathology following a second bout of eccentric contractions. In spite of the presence of histopathology, there were no reductions observed in quadriceps muscle strength following the bout of exercise. Given the shortcomings of histopathology in explaining the strength losses, reported reductions in maximal Ca2+-activated force production by single fibers are our best evidence to date for damage to force-bearing structures contributing to the strength loss. In the single-fiber preparation, the excitationcontraction coupling process can be bypassed by controlling the intracellular Ca2+ level either pharmacologically or directly. Thus, a reduced force production during exposure to a supramaximal level of intracellular Ca2+ can be attributed with certainty to damage or alteration of force-bearing structures. Unfortunately, single-fiber maximal Ca2+-activated force data are not available for human or animal muscles injured in vivo, only for rodent muscles or fibers injured in vitro. We have reported the maximal Ca2+-activated force of fibers isolated from muscles injured in vitro to be reduced by 34% while strength of the muscle from which the fibers were isolated was down by 69%.20 Thus, damage to forcebearing structures could at best account for half of the muscles loss of strength; more than likely this number is an overestimate because the single-fiber
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preparation removes the potential for lateral force transmission to neighboring fibers.10 Using single fibers isolated from a mouse muscle, Balnave and Allen2 reported that maximal Ca2+-activated force was not significantly affected following ten eccentric contractions in which the isolated fibers were stretched to 125% of optimal fiber length (Lo). The maximal isometric force reduction in these fibers was modest though (ie, 28%). In this same study following a protocol reducing maximal isometric force production by 70% (ie, 30 eccentric contractions in which the fibers were stretched to 150% of Lo), the maximal Ca2+-activated force was reduced by 55%. Thus, almost all ( 80%) of the strength loss in this protocol could be accounted for by damage to force-bearing structures within the fiber. To summarize the data to date on single fibers studied following injury, the data indicate that damage to force-bearing structures within the fibers can account for a widely varying proportion of the strength loss (ie, from none in one set of experiments to almost all of the strength loss in another). Before we can estimate the contribution that damage to force-bearing structures play in the strength loss in intact animal or human muscle models, maximal Ca2+-activated force data are needed on fibers injured using these models to ensure that fiber length is constrained within anatomical limits during the contractions. It is likely that stretching of muscle fibers to nonphysiological lengths (ie, 130% Lo) as is possible under in vitro conditions may predispose the force-bearing structures to damage.

Failure to Activate Intact Force-Generating Structures

This category of mechanisms includes those resulting in a failure of excitation-contraction (EC) coupling. For the purposes of our discussion, we define EC coupling as the sequence of events that begins with the release of acetylcholine at the neuromuscular junction and finishes with the release of Ca2+ from the sarcoplasmic reticulum (SR). Figure 3 depicts the anatomical structures and biological events in the EC coupling pathway. There are a number of studies dating back to the late 1970s and early 1980s suggesting that EC coupling failure occurs following eccentric exercise in humans (eg, Davies and White,5 Edwards et al6). In these studies, force produced by injured muscle during low-frequency electrical stimulation was depressed to a greater relative extent than that during highfrequency stimulation. These observations were interpreted to indicate that SR Ca2+ release was depressed at the lower stimulation frequencies, and thus a failure in the EC coupling pathway had occurred. The relative contribution of the EC coupling failure to the strength loss following eccentric contractions was not however investigated until the 1990s. The first study showing definitive evidence for EC
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FIGURE 3. Cartoon drawing of the excitation-contraction coupling pathway. The pathway starts with the release of acetylcholine by the -motoneuron at the neuromuscular junction. The resulting action potential passes along the plasmalemma until it goes deep into the fiber via the t-tubule. Depolarization of the t-tubular membrane causes a conformational change of the voltage sensor. This conformation change is communicated by a still undetermined means to the sarcoplasmic reticulum Ca2+ release channel so that the channel opens and Ca2+ is released into the sarcoplasm where it can bind to troponin and initiate cross-bridge cycling.

coupling failure was that of Warren et al.23 Soleus muscles isolated from mice were injured using 20 eccentric contractions; the muscles were then exposed to a bathing medium containing caffeine at a level high enough to induce contraction. Caffeine acts to increase free cytosolic Ca2+ levels ([Ca2+]i) in muscle fibers by promoting opening of the SR Ca2+ release channel (Figure 3). Thus, the force elicited during caffeine exposure is not dependent on acetylcholine release at the neuromuscular junction, action potential conduction along the plasmalemma or t-tubules, nor communication of the depolarizationinduced conformational change in the t-tubular voltage sensor to SR Ca2+ release channel. In the experiments of Warren et al,23 if a reduction in the caffeine-elicited force had been observed, it would have been interpreted to mean that damage to forcebearing elements or intrinsic SR dysfunction, or both, had occurred. However, caffeine-elicited force of the injured muscles was not different from that of control muscles despite the fact that maximal isometric strength was down by 43% in the injured muscles (versus 4% for the controls). These data were interpreted to mean that EC coupling failure did occur in this in vitro injury model and that EC coupling failure could account for most of the isometric strength loss with minimal evidence for contributions from damage to force-bearing elements or intrinsic SR dysfunction, or both.23 The findings of Warren et al23 were confirmed and expanded upon in two studies by Balnave and
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colleagues.2,3 Using the single-fiber preparation previously described, these researchers were the first to show that muscle fiber [Ca2+]i during tetanic stimulation was depressed following performance of eccentric contractions. In muscle fibers losing a moderate amount of their strength (28%), the [Ca2+]i during tetanic stimulation could be returned to normal by adding low levels of caffeine to the media bathing the fibers. This latter observation indicated that the site of the EC coupling failure must lie above that of the SR Ca2+ release channel because the channel could respond normally if provided with an adequate stimulus (ie, electrical stimulation plus caffeine). Our findings plus those of Balnave and colleagues2,3 were limited in that the EC coupling failure may have been a transient event that only accounts for some strength loss in the first few hours following injury or that the EC coupling failure may represent some artifact of the in vitro preparation (eg, overstretching of the fibers). We sought to overcome these limitations by employing our in vivo model for inducing injury to the anterior crural muscles of mice; at 014 days after injury, injured and contralateral control extensor digitorum longus (EDL) muscles were excised and tested in vitro for EC coupling failure.12 Immediately and three days after injury (ie, times when maximal isometric strength of the EDL muscle was down by 51%), muscle fiber [Ca2+]i was measured during tetanic electrical stimulation and found to be reduced by 2545% compared to control muscles. These findings indicate that previous reports of EC coupling failure were not an artifact of the in vitro injury model nor was the EC coupling failure a transient phenomenon. Though a reduced muscle fiber [Ca2+]i observed during electrical stimulation is definitive evidence for EC coupling failure, it is difficult to predict how a given reduction in fiber [Ca2+]i will impact muscle strength. The effect is highly dependent on the absolute [Ca2+]i during contraction as can be seen in the force:[Ca2+]i curve depicted in Figure 4. If [Ca2+]i during contraction is normally well above the concentrations on the steep portion of the force:[Ca2+]i curve (eg, 5 M in Figure 4), a reduction in [Ca2+]i due to an EC coupling failure may have no effect on force production. However, if the [Ca2+]i during contraction is normally on the steep portion of the force:[Ca2+]i curve (eg, 23 M in Figure 4), muscle fiber force would be markedly affected when a reduction in [Ca2+]i occurs. Unfortunately, it is very difficult to obtain accurate estimates of absolute [Ca2+]i in living muscle fibers and thus, it is difficult to estimate how a depressed Ca2+ release due to EC coupling failure will affect force production. In the study of Ingalls et al,12 we estimated the contribution of the EC coupling failure to the strength loss following in vivo injury by exposing the
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CLINICAL COMMENTARY

FIGURE 4. Force:[Ca2+]i relationship for a chemically skinned mouse extensor digitorum longus muscle fiber. The [Ca2+]i values on the x axis are displayed using a log scale. The effect on force of a reduced free cytosolic Ca2+ levels ([Ca2+]i) resulting from an excitation-contraction coupling failure is highly dependent on the normal [Ca2+]i during contraction. For example, a reduction of 1 M has minimal effect on force production if the [Ca2+]i during contraction is normally 6 M, but the effect is large if the [Ca2+]i during contraction is normally 3 M.

isolated muscles to pharmacological agents (ie, caffeine or 4-chloro-m-cresol) that act on the SR Ca2+ release channel to increase [Ca2+]i. The forces elicited by these agents were down moderately ( 11 21%) compared to the maximal isometric strength reduction ( 51%) at zero to five days postinjury. Based on the disproportionate percentage reduction in the force elicited by the pharmacological agents compared to reduction in isometric strength, we estimated that the EC coupling failure could account for 5775% of the isometric strength deficit in the first five days after injury. If, to the contrary, we had observed the same percentage reduction in pharmacologically induced force as we did in isometric strength, then we would have concluded that EC coupling failure accounted for little to none of the isometric strength loss. The above data indicate that EC coupling failure does occur in the contraction-injured muscle but the data do not indicate the site of failure. We have attempted to identify the site but have been only partly successful because the EC coupling pathway is not fully understood. Specifically, the means by which the depolarization-induced conformational change of the t-tubular voltage sensor causes the SR Ca2+ release channel to open has not been established. Our data on Ca2+ release rates from SR vesicles isolated from injured muscles indicate that the intrinsic capacity of the SR to release Ca2+ is not adversely affected, at least not in the first 24 hours after injury.12 Another logical site for the EC coupling failure would be the plasmalemma, given the ample evidence for plasmalemmal damage following performance of eccentric contractions (Warren et al22). However, we
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FIGURE 5. Potential site(s) of the excitation-contraction (EC) coupling failure in the eccentric contraction-injured muscle. Our data so far indicate that neuromuscular junction function, plasmalemmal action potential-conducting capacity, and intrinsic sarcoplasmic reticulum function are relatively normal in the first 24 hours after injury and, thus, do not contribute to the EC coupling failure. Similarly, the ability of the t-tubule to conduct action potentials does not appear to be harmed but those data must be considered as preliminary. By default, we offer that the EC coupling failure results from the depolarization-induced voltage sensor conformational change failing to be communicated to the sarcoplasmic reticulum Ca2+ release channel.

have assessed the capacity of injured muscle fibers to conduct action potentials along their plasmalemma and found it to not be significantly altered.21 Finally, we have conducted a preliminary investigation of t-tubular membrane function in injured muscle. T-tubular membrane function in the injured muscle appeared normal when probed with a high extracellular concentration of potassium used to induce contraction by depolarizing plasmalemmal and t-tubular membranes.12 Thus, by process of elimination, we have hypothesized that the failing site in EC coupling pathway may be the t-tubular voltage sensor or the communication between it and the SR Ca2+ release channel, or both.12 Figure 5 summarizes our current knowledge of the potential sites of EC coupling failure for the contraction-injured muscle.

Frank Loss of Force-Generating or Force-Transmitting Structures, or Both

In theory, a rapid increase in the degradation of force-bearing protein structures could contribute to the initial reduction in strength following injury. Also, in the days following initiation of the injury, increased contractile protein degradation or decreased protein synthesis, or both, could contribute to an additional loss of strength. There is little evidence however to suggest that any of these scenarios occurs. First of all, the degradation rate of muscle protein is not increased immediately after in vivo
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FIGURE 6. Changes in strength, contractile protein content, and protein degradation rate in the first 28 days following in vivo eccentric contraction-induced muscle injury. The strength loss immediately after injury cannot be accounted for by a change in whole muscle protein metabolism. Furthermore, strength begins to recover in the days following injury even though contractile protein is being lost over that same time frame. By two weeks postinjury, the relationship between strength and contractile protein content is reestablished and the rate of recovery for strength becomes limited by that for contractile protein content. Data are compiled from Ingalls et al11,12 and Lowe et al.14

FIGURE 7. Estimated contributions of excitation-contraction (EC) coupling failure, decreased contractile protein content, and physical damage of force-bearing elements to the strength loss observed in our in vivo model of muscle injury. In the first five days after injury, EC coupling failure can account for 5775% of the strength loss. By five days postinjury, the EC coupling failure is diminishing and a gradual loss of contractile protein explains an increasingly larger proportion of the strength loss. The entire strength loss from 14 days postinjury and on can be explained by a decreased contractile protein content. Estimates are based on data compiled from Ingalls et al1,12 and Lowe et al.14

CLINICAL COMMENTARY

injury nor for at least the next six hours (Figure 6).14 Neither total nor contractile (ie, actin and myosin heavy chain) protein content is altered over that same time period, so none of the rapid loss of strength following injury initiation can be attributed to changes in these protein contents.11,14 However, these whole-muscle protein metabolism measures cannot detect changes in the content of a minor protein that plays a key role in force generation or transmission, or both. For example, a rapid loss of the cytoskeletal protein, desmin, has been observed shortly after the onset of an injurious eccentric contraction protocol.13 It is unknown whether desmin plays a role in sarcomeric force transmission although it is assumed that it may because of the proteins association with the z-line. There is good evidence for a loss of muscle protein in the days following initiation of the injury. In our in vivo injury model, the protein degradation rate is increasing by one day postinjury and by two days has plateaued at a rate 60% greater than normal; the elevated rate is maintained for at least three more days (Figure 6).14 As a result, there is a progressive loss of contractile protein beginning at about one day postinjury; actin and myosin heavy chain contents are reduced by 20% five days after initiation of the injury.11 Contrary to what one might expect, the loss of contractile protein has no adverse effect on muscle strength. In fact, muscle strength is beginning to recover by three to five days postinjury even
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though contractile protein content is still decreasing (Figure 6).11 By two weeks postinjury, the strength deficit that remains can be mathematically accounted for by the reduction in contractile protein content. Furthermore, the recovery in strength from two weeks on parallels the recovery in contractile protein content, thus suggesting a causal relationship between the two measures over that time period.

Summary
In this concluding section, estimates are provided of the relative contributions of the three categories to the strength loss following contraction-induced injury (Figure 7). These estimates are based on data pooled from three comprehensive studies of in vivo muscle injury in which 824 muscles were studied.11,12,14 Over the first three days of injury, most ( 75%) of the strength loss is ascribed to a failure of the EC coupling pathway. The remainder of the strength loss, at least for the first day or two, is attributed to damage of force-bearing elements within the muscle. By three days postinjury, the part of the strength deficit unaccounted for by EC coupling failure is attributed to a decreased contractile protein content, which most likely results from removal of damaged force-generating structures. The EC coupling failure is diminishing by five days postinjury and is practically nonexistent by 14 days postinjury. Over that period, the proportion of the strength
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deficit accounted for the contractile protein loss increases from 4045% to almost 100%. In conclusion, it should be apparent to the reader by now that there is no easy explanation for the strength loss following eccentric contractions. The strength loss appears to result from a complex interaction of mechanisms, the details of which remain to be ascertained. Finally, we again wish to point out that our understanding of the strength loss comes mostly from studies of mouse muscle in which the contractions have been elicited through maximal electrical stimulation. It is thus possible that the strength loss induced by this model may differ qualitatively from that elicited by submaximal, voluntary eccentric contractions performed by humans.

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10. Huijing PA. Muscle as a collagen fiber reinforced composite: a review of force transmission in muscle and whole limb. J Biomech. 1999;32:329345. 11. Ingalls CP, Warren GL, Armstrong RB. Dissociation of force production from MHC and actin contents in muscles injured by eccentric contractions. J Muscle Res Cell Motil. 1998;19:215224. 12. Ingalls CP, Warren GL, Williams JH, Ward CW, Armstrong RB. EC coupling failure in mouse EDL muscle after in vivo eccentric contractions. J Appl Physiol. 1998;85:5867. 13. Lieber RL, Schmitz MC, Mishra DK, Friden J. Contrac tile and cellular remodeling in rabbit skeletal muscle after cyclic eccentric contractions. J Appl Physiol. 1994;77:19261934. 14. Lowe DA, Warren GL, Ingalls CP, Boorstein DB, Armstrong RB. Muscle function and protein metabolism following initiation of eccentric contraction-induced injury. J Appl Physiol. 1995;79:12601270. 15. McCully KK, Faulkner JA. Characteristics of lengthening contractions associated with injury to skeletal muscle fibers. J Appl Physiol. 1986;61:293299. 16. McCully KK, Faulkner JA. Injury to skeletal muscle fibers of mice following lengthening contractions. J Appl Physiol. 1985;59:119126. 17. Ogilvie RW, Armstrong RB, Baird KE, Bottoms CL. Lesions in the rat soleus muscle following eccentrically biased exercise. Am J Anat. 1988;182:335346. 18. Sayers SP, Clarkson PM, Rouzier PA, Kamen G. Adverse events associated with eccentric exercise protocols: six case studies. Med Sci Sports Exerc. 1999;31:1697 1702. 19. Warren GL, Hayes DA, Lowe DA, Armstrong RB. Mechanical factors in the initiation of eccentric contraction-induced injury in rat soleus muscle. J Physiol. 1993;464:457475. 20. Warren GL, Hayes DA, Lowe DA, Williams JH, Armstrong RB. Eccentric contraction-induced injury in normal and hindlimb-suspended mouse soleus and EDL muscles. J Appl Physiol. 1994;77:14211430. 21. Warren GL, Ingalls CP, Shah SJ, Armstrong RB. Uncoupling of in vivo torque production from EMG in mouse muscles injured by eccentric contractions. J Physiol. 1999;515:609619. 22. Warren GL, Lowe DA, Armstrong RB. Measurement tools used in the study of eccentric contraction-induced injury. Sports Med. 1999;27:4359. 23. Warren GL, Lowe DA, Hayes DA, Karwoski CJ, Prior BM, Armstrong RB. Excitation failure in mouse soleus muscle injured by eccentric contractions. J Physiol. 1993;468:487499. 24. Warren JA, Jenkins RR, Packer L, Witt EH, Armstrong RB. Elevated muscle vitamin E does not attenuate eccentric exercise-induced muscle injury. J Appl Physiol. 1992;72:21682175.

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