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MINIREVIEW Muscle Fatigue: Conduction or Mechanical Failure? KRISTEN A. LUCKIN,* *Department t Division

MICHEL C. BIEDERMANN,* SHARON A. JUBRIAS,* WILLIAMS,~ AND GARY A. KLUG*”

JAY H.

of Exercise and Movement Science, University of Oregon, Eugene, Oregon 97403; and of Health and Physical Education, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061

Received August 9, 1991 It is well documented that repeated voluntary activity or electrical stimulation of skeletal muscle results in a decline in force production or power output. However, the precise physiological causes of “muscle fatigue” are not yet well understood. It is conceivable that the mechanism(s) may lie either in the conduction of action potentials in the central and peripheral nervous systems or in the transformation of the electrical event into mechanical force production by the muscle itself. In fact, none of the components of the electrical pathway from generation of impulses in the brain to their conduction over the neuron and the excitable membranes of the muscle can as yet be ruled out as potential contributors to the fatigue process. Relative to that on conduction failure, more information exists concerning the possibility that a defect in the excitation contraction coupling process in skeletal muscle, e.g., intracellular acidosis, inadequate supply of energy for contraction, or a disruption in Ca” homeostasis may also be significant in compromising force production following sustained activity, Despite this, the amount of conflicting data derived from these experiments has hindered the resolution of this question. In the future more attention must be given to such issues as the type of activity used to elicit fatigue and the fiber composition of the muscles studied. This is imperative as these factors clearly impact the nature of correlations between the biochemical and physiological events in muscle that are required to support prospective fatigue mechanisms. 0 1991 Academic Press, Inc.

In the last several decades considerable interest has arisen regarding the mechanisms underlying “muscle fatigue” which occurs during sustained activity and is characterized by a reduction in force. Such studies are complicated by numerous factors not the least of which is the difficulty in attaching a consistent definition to the term. Although numerous suggestions have been made, perhaps the most widely used definition is that of Edwards (1) who states that fatigue is “the inability to maintain force or power output during sustained or repetitive contractions.” This statement may be adequate for those who assign some type of dysfunction ’ To whom correspondence should be addressed. 299

0885-4505/91 $3.08 Copyright 8 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.

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in skeletal muscle itself as the critical determinant in the fatigue process. However, it is likely to be quite unsatisfactory to investigators studying other mechanisms since repetitive voluntary activity can produce changes in the nervous system that can compromise muscle function well in advance of any detectable loss in force (2). Thus, it is apparent that precise identification of a point at which fatigue begins is one of the initial obstacles encountered in attempts to attribute etiological significance to alterations in muscle or the nervous system. The majority of studies investigating fatigue mechanisms have concentrated on intramuscular events. This is likely related to the fact that the decline in force or power in skeletal muscle used to define fatigue can be measured with little difficulty. Despite this advantage, such studies on skeletal muscle are complicated by some of its inherent characteristics. A discussion of some of these factors is useful with regard to understanding how they can influence the experiments and confound interpretation of the results. Factors Affecting the Conduct of Fatigue Studies The causes of the decrease in contractile force in response to exercise are tied to the intensity and duration of the activity. This apparent sensitivity complicates the investigative process as two different activity paradigms can produce identical reductions in power or force in the face of dramatically different intramuscular environments. This is most easily illustrated in comparisons between high intensity exercise sustained for brief periods with that which takes place at low intensity for a protracted period of time. In the former case there can be significant alterations in pH and the concentrations of various metabolites (3), whereas such perturbations seldom occur in the latter. The importance assigned to the type of activity used to produce muscle fatigue is also relevant in experiments with electrical stimulation. It is now accepted that depressed force production caused by electrical stimulation can be grouped into at least two types whose characteristics are dictated by stimulus frequency (4). They include low frequency (~25 Hz or less) characterized by a sustained loss of force and high frequency (-75 Hz or more) where contractility recovers rapidly. Not surprisingly, the mechanisms responsible for these two phenomena are also thought to be different (5,6). These caveats surrounding the importance of exercise intensity/duration and stimulation frequency suggest that any conclusions regarding the mechanisms of muscle fatigue should not be made without relating them to the type of activity employed. Unfortunately, this issue is too often ignored. Much of the current experimental evidence on fatigue has been derived from experiments on whole muscle. This model provides the distinct advantage of permitting correlations between mechanical and biochemical events that assist in developing cause and effect relationships. However, it is not without its limitations. During dynamic exercise all the fibers of an active skeletal muscle are seldom simultaneously recruited (4,7). As a result, analyses performed on whole muscle are likely to include fibers that have been recruited as well as those that have remained quiescent. This problem can be ameliorated to some extent by external stimulation of the muscle with supramaximal electrical pulses. However, as is the

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case with all artificial stimulation, this model is often limited in its ability to easily mimic the precise stimulation patterns that the muscle experiences in viva. Yet another concern in this area is the heterogeneity of the structural and functional characteristics of the fibers contained in mammalian skeletal muscles (8). This is particularly true with regard to the mitochondrial volume density of the individual fibers. This factor is of considerable importance in fatigue studies as it is well correlated with the ability of muscle to maintain force during repetitive activity (9). The degree of variability in a single muscle is very profound as Reichmann and Pette (10) have demonstrated a broad spectrum of activities (fiveto eightfold differences) in mitochondrial marker enzymes even within a group of fibers that have been histologically classified as Type II. It is also well known that differences exist between fiber types with regard to the ability of short-term stimulation to potentiate twitch tension. Specifically, tetanic (11) and even low-frequency stimulation (12) can potentiate the isometric force production of fast skeletal muscle (posttetanic or staircase potentiation) whereas, the response is much less pronounced or even absent in muscle of the slow type (13). This phenomenon, which may be related to phosphorylation of myosin light chains (11,14) would quite naturally oppose any processes at work to compromise force in fast-twitch fibers, but would not be operative in slow muscle. Thus, discrepancies in mitochondrial content and potentiation characteristics between muscles and the fibers they contain cannot be ignored in studies of fatigue. This brief discussion of some of the problems inherent in experiments investigating the mechanisms of fatigue is by no means exhaustive. However, it raises the point that the results of fatigue studies are often dependent entirely on the experimental design. Thus, care must be taken when extrapolating the results to the general phenomenon. The scope of this review does not permit in-depth analysis of these discrepancies nor discussion of the conflicts they create. Rather, it is hoped that readers new to this area will become aware of the potential sites of muscle dysfunction that contribute to the appearance of fatigue in skeletal muscle during sustained muscle activity. For more detailed information on fatigue mechanisms the readers are encouraged to investigate articles by Edwards and colleagues (15) and the proceedings from the recent conference of the French “Association des Physiologistes” sponsored by the “Institut National de la Sante et de la Recherche MCdicale” (INSERM) (16). The Pathway of Muscle Contraction Voluntary muscle contraction consists of a series of electrical, chemical, and mechanical events originating with the creation of a stimulus in the central nervous system and ending with the production of force in skeletal muscle. Dispersed throughout this pathway are a number of sites where fatigue could originate via events ranging from a decline in motor unit firing frequency (17), to failure of transmission at the neuromuscular junction (18), to disruption of normal intracellular Ca2+ homeostasis (19) (see Table 1). These mechanisms, which may be

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TABLE 1 Possible Events of Muscle Fatigue Mechanical events

Conduction system Central drive Decreased stimulation rate Decreased post-synaptic transmitter sensitivity Psychological factors

Metabolites Lactic acid and intracellular pH High energy phosphates and carbohydrates

Neural conduction Axonal block Decreased nerve conduction velocity

Intracellular calcium Sarcoplasmic reticulum Ca*’ uptake Ca*+ release

Neuromuscular junction Decreased neurotransmitter release Wh) Depressed motor end-plate excitability

Extracellular

calcium

Myofilaments

Sarcolemma and T-tubules Ionic gradiant changes Decreased membrane conduction velocity Decrease action potential amplitude

either extra- or intramuscular in nature, could act alone or synergistically (20, 21). Evidence exists indicating that the transmission of electrical impulses which trigger contraction can be compromised in some types of activities (22). Conversely, Merton (23) demonstrated a decline in force production in the absence of any alteration in the muscle action potential suggesting that the mechanism(s) of fatigue could also be assigned directly to the muscle. In light of these observations, we have chosen to divide the discussion of potential mechanisms into two parts. The first, which will be referred to as conduction failure, includes the electrical events beginning with the generation of the neural action potential by the central nervous system and extending through its propagation via the neuromuscular junction (NMJ), the sarcolemma (SL), and ultimately the transversetubular (IT) system. The second, mechanical failure, begins with the transfer of the electrical signal from the IT to the sarcoplasmic reticulum (SR) and extends to the interaction of the contractile proteins actin and myosin. The latter category will also include the metabolic pathways responsible for supplying the energy required to sustain contraction. CONDUCTION FAILURE

Central Drive and Neuron Conduction One of the fundamental mechanical characteristics of skeletal muscle is that the magnitude of force generation is dependent on the stimulation frequency originating in higher motor centers of the brain (24-26). That is, the higher the

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stimulation frequency, the greater the tension generated up to a maximum frequency which is determined by the type of motor unit in question (27). Following a maximal voluntary effort in several leg muscles, Grimby et al. (27) observed no change in firing frequency in slow-twitch motor units, whereas that of neurons innervating fast-twitch units declined by up to two-thirds. Similar observations have been found by others (28,29). Although it cannot be ruled out that this decline is due to decreased central drive, currently it is difficult to support this possibility. However, it has been suggested that frequency declines because the postjunctional membrane or sarcolemma are less excitable. (22,30,31). In light of the frequency dependence of force production, it would appear that a decline in rate of stimulation would contribute to fatigue. However, a number of investigators have suggested that this change, together with the prolongation of the twitch time that occurs simultaneously, may prolong the ability of fast-twitch units to sustain force, albeit at lower frequencies (22,24,27,28). Blomstrand et al. (32) have provided evidence that prolonged, low intensity exercise by humans (1.5-5 h) increases the concentration of the neurotransmitter 5-hydroxytryptamine (5HT) which is thought to be responsible for causing the state of tiredness or sleep. As a result, they suggest that this effect might contribute to the perception of fatigue in exercising subjects. This highlights the possible role played by psychological factors in “central fatigue.” Although these factors are potentially important, they are beyond the scope of the present paper and the reader is directed toward other reviews specifically addressing these issues (33,34). Neurotransmission failure at axonal branch points has been observed in studies using electrical stimulation of mammalian muscle (22,35-37). Kernel1 and colleagues (38-40) also found that changes in the excitability of central motor neurones occurred in response to constant current injection. However, no sign of electrical transmission block was observed following 60-90 s of sustained maximal voluntary contractions (MVC) (23,29,41). Currently, the technical difficulties associated with differentiating failure in neural conduction from that related to the neuromuscular junction (NMJ) make conclusions regarding the contribution of neuronal transmission failure to muscle fatigue equivocal. Neuromuscular

Junction

The neuromuscular junction is the synapse that links a motoneuron and its corresponding skeletal muscle fiber. Transmission failure at the NMJ has been reported in rat muscle in vitro and in situ at stimulation frequencies of approximately 50-100 Hz, (22,42) perhaps because of diminished neurotransmitter release or reduced end-plate excitability (25). Using diaphragm muscle in vitro, Kuei et al. (25) demonstrated that decreasing the Ca*‘/Mg*+ concentration in the bath and elevating the temperature increased the contribution of neurotransmission failure to fatigue, although it could not be determined if this was axonal or junctional in nature. Early experiments on NMJ failure hypothesized it to be the most important factor in fatigue evoked early in the performance of MVC (43) in high threshold (fast) motor units. However, these findings were questioned by

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Bigland-Ritchie (2) who concluded that NMJ failure did not contribute of force during voluntary contractions.

to the loss

Sarcolemma and T-Tubules The sarcolemma membrane, separating the extracellular space from the myoplasm, conducts action potentials from the neuromuscular junction to the calciumrich sarcoplasmic reticulum (SR), via the ‘IT. Alterations in ionic gradients across the SL have been observed with muscular activity (44). It has been suggested that this effect may depress conduction velocity of the SL as well as the amplitude of the action potential (4546). A reduced SL action potential has been shown in single muscle fibers in response to sustained high-frequency stimulation (22,47). However, it is unclear whether these findings are physiologically relevant, as Benzanilla et al. (47) demonstrated that its reduction had no effect on peak tension output in single muscle fibers. In addition, Metzger and Fitts (48) showed that high-frequency (75 Hz) and low-frequency (5 Hz) stimulations produced virtually identical depressions in SL action potentials even though there was a much greater reduction in force at the higher frequency. Thus, it is unlikely that changes in surface membrane properties alone can explain the attentuation of contraction under these conditions. Changes in the ionic composition of the myoplasm common to fatigue (loss of K+ and gain in Na+, Cl-, and Hz0 intracellularly) (49) can be simulated in vitro by raising the extracellular [K+] (46). This treatment, which would compromise the propagation of the action potential, would be most significant at the level of the TT where diffusion limitations might exist (50). The significance of altered ion gradients in force output is supported by the work of Howell and Snoedowne (51) who found a decline in peak tetanic tension in vitro when the extracellular [Ca”] was increased. They concluded that this effect was due to a slowing of the action potential in the TT. Bianchi et al. (52) have also postulated that highfrequency stimulation leads to accumulation of Ca2’ in the IT and disruption of E-C coupling, although this possibility has recently been questioned (53). Collectively, these data indicate that mechanisms related to IT and SL do exist that could compromise the activation of muscle and contribute to fatigue. However, it remains to be demonstrated that such conditions are actually duplicated in vivo. MECHANICAL EVENTS Of all areas of research on the etiology of fatigue, the possibility that its basis may be associated in some manner with muscle metabolism has undoubtedly received the most attention. The traditional hypothesis has assumed that the accumulation of metabolic intermediates hinder the contractile process although the depletion of some specific metabolites may also be contributory (54). The compounds most often implicated are various intermediates generated directly or indirectly by the contractile machinery itself (e.g., ADP, Pi, and its diprotonated species H,PO; , AMP, IMP) and lactic acid (LA) which, via its dissociable H+, influences cell pH. It has been demonstrated in vitro that each of these metabolites directly alters either the actin-myosin interaction responsible for force production or the biochemical pathways involved in supplying the energy required to sustain

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that force (55-59). As a result, much experimentation has been performed to investigate the possibility that a correlation exists between the cellular concentration of these metabolites and reduced force output. Intramuscular Acidosis High-intensity, short-duration work results in a decline in muscle pH presumably derived from the accumulation of LA (5560-67). Using short-term, high-intensity exercise in humans, Sahlin et al. (3,68) reported decreases in pH from 7.0 at rest to 6.4 at exhaustion. More recently, 31P NMR experiments have shown muscle pH to fall to levels below 6.2 (69). I n vitro, such acidotic conditions: (1) increase the amount of Ca*+ necessary to obtain a prescribed amount of tension (55,70); (2) decrease maximal twitch tension (55,59,70); and (3) decrease the maximum shortening velocity of the fiber (59). These and other data pointing to a deleterious effect of decreased pH on muscle function have given rise to several hypotheses concerning fatigue mechanisms. Dawson et al. (71) suggested that depressed pH causes acidification of Pi to the diprotonated species H2PO; resulting in interference of cross-bridge formation, although this hypothesis remains controversial (20,72-75). A second possibility is that low pH may compromise excitationcontraction coupling in some manner related to a disruption in normal Ca*’ metabolism (48,62,76,77), a suggestion that will be discussed below. Despite these data, acidification of the muscle cell is not readily accepted as a fatigue mechanism. In numerous studies where a correlation between force and [Hf] was made during recovery from muscle stimulation, decreased pH was found to be an unimportant contributor (78-82). These findings were confirmed in studies employing short, high-intensity exercise bouts to fatigue (69,83). In addition, studies with McArdle’s patients, who are unable to metabolize glycogen, demonstrated that these subjects had a low exercise tolerance despite the absence of any marked accumulation of lactic acid (see Ref (84)). These findings question the legitimacy of decreased pH as a fatigue mechanism in those activities (high-intensity exercise or stimulation) which do result in significant production of lactic acid. Thus, it follows that this mechanism does not play a role in exercise of lower intensity and longer duration since such activity rarely results in cell acidosis (85,86). High Energy Phosphates The energy required to sustain muscle contraction is derived from the hydrolysis of ATP. As a result, a number of investigations have examined the possibility that fatigue may be linked to the inability of the various metabolic processes to provide an adequate supply of this high energy phosphate or its precursors. The observation that the fatigue resistance of muscle is correlated with its mitochondrial volume density (8) adds credibility to this hypothesis. Experiments with rats (87-SS), dogs (89), and horses (90) have demonstrated structural alterations in muscle mitochondria following exercise of different intensities and durations. Furthermore, it has been shown that oxygen consumption is depressed in isolated mitochondria and fibers taken from rats following prolonged exercise (91,92) and in muscle homogenates obtained from horses after

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short, high-intensity work (92). It is possible that such alterations are indicative of a reduced ability of mitochondria to produce ATP which could contribute to the onset of fatigue, although no concrete evidence currently exists supporting this hypothesis. Early work by Dill et al. (93) and others (63,83,94,95) using traditional biochemical techniques indicates that the loss of force production can indeed be directly linked to depletion of high energy phosphates. More recently, using NMR, it has been suggested that fatigue is well correlated with increased inorganic phosphate and depressed ATP (96,97). Conversely, others have shown that, during recovery, force production returns to normal in advance of high energy phosphates (15,86,98). Cooke and Pate (99)) using an in vitro skinned fiber technique, showed that exogenous AMP, IMP, adenosine, inosine, ammonia, creatine, pyruvate, and lactate had no effect on the fiber’s contractile properties. Collectively, these data indicate that the issue of the importance of high energy phosphates or metabolites associated with their production in fatigue remains unresolved. In spite of the controversy surrounding muscle high energy phosphate concentrations, a correlation does exist between the inability to sustain exercise at 6085% of maximal oxygen consumption and loss of muscle glycogen (94,100-104). Additional support for a role for glycogen in this type of exercise comes from studies showing that endurance time in whole body exercise can be prolonged by dietary manipulations that elevate the level of muscle glycogen in the working muscles (105-109). The precise mechanism explaining why muscle carbohydrates are performance limiting is unknown. It is unlikely that energy availability is the critical factor as even when glycogen is depleted, creatine phosphate is approximately 50% of resting values and ATP is within the normal range (7274,81,82,94,95,110). Excitation-Contraction Coupling Intracellular Ca2 +. In the past several years, the possibility that muscle activity may directly result in the failure of some constituent(s) of excitation/contraction coupling has received considerable attention. This line of research proposes that fatigue may occur when the action potential in the ‘IT fails to release sufficient Ca2+ from the SR or if that Ca2+ released does not adequately activate the contractile elements. This could occur if the fatiguing activity: (1) resulted in insufficient loading of SR with Ca”; (2) altered the SR Ca2+ release mechanism; or (3) decreased the sensitivity of the contractile apparatus to Ca2+. The possibility of a disruption in the ability to regulate intracellular Ca2’ following repetitive activity is supported by the observations showing that an increase in twitch relaxation time accompanies depressed force output in fatigued muscle (50,111-113). Relaxation time is thought to be dependent on the capacity of the SR to regulate Ca2+ (50) implicating this organelle as a potential regulatory site in fatigue. Assessment of SR Ca2+ uptake and ATP hydrolysis by the ATPase pump protein in isolated vesicles has repeatedly shown that both prolonged exercise and shortterm, high-intensity exercise reversibly depresses SR function (19,95,114-l 19). Single fiber studies with both high- and low-frequency stimulations also support

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the ability of activity to adversely affect the capacity of SR to regulate intracellular Ca2’ (120,121). Although the mechanism for these observations is yet to be elucidated, recent evidence suggests that the depressions may be related to a structural alteration in the ATPase protein (115,122). Other factors may also contribute to the disruption of SR function. For example, H+ accumulation increases the amount of Ca2’ bound to the sarcoplasmic reticulum (76) as well as inhibits the SR ATPase (123). These mechanisms could be operative under conditions of high-intensity exercise where pH declines markedly (9%

If any of these effects on SR result in the inability to adequately load it with Ca’+, it is possible that the amount released during a transient would be insufficient to properly activate the contractile elements. Evidence does exist that muscle activity can indeed compromise Ca2+ release (see Ref. (124) for an excellent review of the proposed mechanisms on SR Ca2+ release). Recent experiments with frog single fibers stimulated to fatigue at high frequency have shown a reduced Ca2+ transient as well as depressed force production (120,125). These findings are consistent with those showing a reduced rate of Ca*+ release from SR isolated from rat muscle following a single bout of prolonged submaximal exercise (114). In the latter studies, evidence was presented consistent with a modification of the Ca*’ release channel. Additional support for this possibility comes from our recent observation of a decreased sensitivity of the release mechanism to caffeine in electrically stimulated frog single muscle fibers (unpublished observations). Fitts et al. (50) have postulated that a reduced SR Ca*’ release represents either a blockage of TT charge movement or an inadequate SR Ca2+ pool available for release. The fact that exogenously applied caffeine and K+ are able to restore the Ca2+ transient and force production in fatigued single fibers argues against the latter hypothesis (120,121,129,130). It is apparent from these studies that a disruption of SR Ca*+ uptake and release remains a viable mechanism to explain the link between repetitive muscle activity and a decline in force production. Extracellular Ca2+. During activation of skeletal muscle, a net uptake of Ca*+ occurs (131,132). Although voltage-dependent, sarcolemmal Ca2+ channels are located at the level of the TT (133), current opinion holds that Ca2+ stored intracellularly by the SR is the major source used to support contraction. This position is supported by findings that force production is not depressed by removal of extracellular Ca2+ (134) or by addition of Ca2+ channel antagonists (135). It appears that gating of the sarcolemmal Ca”’ channels is slow and that the influx of extracellular Ca2+ .is too small to markedly influence single contractions. Despite these observations, recent evidence suggests that extracellular Ca2+ may indeed influence contractions which are evoked during repetitive activation. Work by Feldmeyer et al. (136) and Garcia et al. (137) show that during repetitive activation, gating of the Ca2’ channels and the magnitude of Ca” entry into the cell are increased. The altered sarcolemma ionic gradients that are associated with fatigue described earlier could also depolarize the TT membrane and promote additional Ca*+ entry (131). When extracellular Ca2’ is removed or replaced by Mg2+ and/or Ca2+ antagonists, the degree of staicase and post-tetanic potentiation is reduced and the characteristics of fatigue are exacerbated (138,139). In addition,

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the Ca*+ channel agonist Bay K 8644, which increases Ca*’ influx, accelerates fatigue (140). These effects do not appear to be related to depletion of cellular Ca*+ or muscle damage since caffeine causes near maximal contractures in fatigued muscles and both twitch and tetanic tensions are fully recoverable. At present, it is not clear as to how extracellular Ca*+ and SL Ca*’ channels might influence contractions during fatigue. Fatigue-induced changes in ‘IT Ca*+ concentration which might impair propagation of the action potential do not seem to occur (53). Also, a direct effect of Ca*+ entry on the contractile apparatus is unlikely since the amount of Ca*+ entering the muscle during each action potential is extremely small compared to that released by the SR. More likely, extracellular Ca*+ exerts some secondary effect on repetitively evoked contractions, possibly by influencing the Ca*+-induced Ca*’ release mechanism (CICR) of the SR. Although the CICR is not thought to be the primary mode of SR Ca*+ release under normal conditions, it may play a more important role under conditions of inhibited Ca*’ release such as that which may occur during fatigue. By reducing Ca*+ entry during repetitive stimulation, this secondary stimulus for SR Ca*’ release may be inhibited. In any case, extracellular Ca*’ and its inflwr may not be a direct factor in the fatigue process, but it is apparent that manipulation of Ca*’ entry does have marked effects on its characteristics. A final point related to the issue of Ca*+ activation of the contractile elements deals with the possibility that the interaction of actin and myosin is itself affected by repetitive activity. The evidence regarding this issue is very limited. It has been demonstrated that H+ ions can compete with Ca*’ for the binding site on troponin which may prove a factor in activity where cell pH is depressed (141). However, Fitts et al. (142) failed to find any change in myofibrillar ATPase activity or maximal shortening velocity in muscles taken from rats exposed to prolonged swimming. In addition, we have recently shown that the pCa/tension relationship does not differ substantially in isolated frog single fibers derived from control muscles and those electrically stimulated to fatigue. Thus, the issue of the direct effect of repetitive activity on the contractile proteins or their interaction remains an open question. SUMMARY The inability to sustain force production in skeletal muscle or to continue exercise for extended periods of time results from failure in a neuromuscular pathway that ranges from activation of the (Y motor neuron to interaction of the contractile proteins. The dysfunction can occur at a single site or at numerous points, either sequentially or concomitantly (143-145). This fact, coupled with the likelihood that the mechanisms of fatigue are heavily influenced by the mode of activity used to produce it, has made the study of this question extremely complex. Unfortunately, experiments investigating fatigue have too often ignored these issues and have treated it as a process whose explanation lies in an activityinduced failure at a single site. This approach has likely contributed to the significant amount of contradictory data in the area. A review of the literature suggests that it would be valuable to present mechanistic hypotheses only after clear identification of the criteria that were used to determine when fatigue actually

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occurred. Furthermore, such conclusions should be discussed only in the context of the precise method of exercise or stimulation employed to produce that type of fatigue. Evidence of a loss of force producing capability in the presence of a diminished muscle action potential indicates that, under some conditions, fatigue can be neural in nature (22,30,31). There has been some progress in the investigation of the possibility of failure in the origination and conduction of action potentials in the central and peripheral nervous system and in the excitable membrane of the skeletal muscle. However, technical difficulties associated with differentiating the site of the transmission block need to be addressed before more specific conclusions can be made about these questions. Furthermore, psychological variables such as motivation (146) and self-efficacy may play a very important role when fatigue is examined in whole-body exercise with human subjects. Clearly, the contribution of all these factors represents a potential fertile area of research. A considerable amount of data exists concerning the importance of alterations in skeletal muscle with regard to the regulation of its own contractile characteristics. These results have been used to formulate the hypotheses that the decreased force production with activity is related to: (1) the accumulation of tissue metabolites; (2) the inability to maintain adequate concentrations of high energy phosphates or carbohydrates; or (3) an inability to activate the contractile proteins perhaps due to a disruption in intracellular Ca2+ homeostasis. A large body of conflicting evidence exists with regard to the contribution of various metabolites and high energy phosphates to the fatigue process. A basis for fatigue involving these compounds has been well documented (15). Nevertheless, recent research, particularly that involving NMR spectroscopy (81,82), has questioned the direct relationship between the process of fatigue and any specific metabolite. What is clear from these experiments is that conclusions about these questions are in large part determined by the experimental conditions. It now appears likely that a common mechanism of fatigue may be a disturbance of Ca*+ homeostasis particularly as it is affected by the uptake and release of Ca*+ from the sarcoplasmic reticulum. These processes have been shown to be affected in a manner that may compromise force in activity models ranging from high- and low-intensity exercise (19,95,115-118) to electrical stimulation of whole muscle (122) and isolated single fibers (120,121). The fact that these perturbations are reversible and that they can be observed with so many different types of activity make this hypothesis one that warrants more investigation. As the progress in research on fatigue continues, three fundamental questions must be answered. The first, which deals with the location or locations of the dysfunction, has been addressed in some detail in this manuscript. However, equally important is the question regarding identification of the stimulus that actually permits or causes changes in sarcoplasmic reticulum function, neuron firing, or some other system that ultimately results in reduced muscle contractility. One such possibility is elevated temperature. It has been recently demonstrated that, no matter what the intensity of the exercise, treadmill exercise to exhaustion in horses (defined as the inability to continue at the required pace) produces muscle temperatures that exceed 42°C (D. Hodgson, personal communications).

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It has also been shown that the contractile characteristics of isolated muscle following electrical stimulation to fatigue (force decline of 50%) are closely tied to the temperature of the muscle bath (147). The capacity to link such variables as temperature with some of the mechanisms described in this paper would do much to contribute to resolution of the questions surrounding this area of research. The third relevant question deals with the issue of identifying the purpose of the decline in force production. Fatigue is often viewed by those who experience it as a negative factor because of the need to reduce the intensity of work or stop it altogether. However, Maier et al. (148,149) have demonstrated with electrical stimulation of muscle in situ that long periods of muscle activity can result in fasttwitch fiber degeneration. These observations suggest that whatever mechanisms are operative to produce fatigue, they may act to downregulate the use of the active muscles so that their structural and functional integrity are not compromised. It is clear that much work remains before the questions regarding the causes of muscle fatigue are firmly established. This work will not only contribute to the answers to the fundamental questions in this area, but it may also significantly advance the understanding of the fundamental physiology and biochemistry of skeletal muscle and the nervous system. ACKNOWLEDGMENTS This work was supported by a grant (AR 39583) from the National Institutes of Health. K.A.L. and M.C.B. were recipients of Systems Training Grants (GM 07257) from the National Institutes of Health.

REFERENCES 1. Edwards RHT. Human muscle function and fatigue. In Human Muscle Function and Physiological Mechanisms. (Porter R, Whelan J, Eds.). London: Pitman Medical, 1984, pp 1-18. 2. Bigland-Ritchie B. EMG and fatigue of human voluntary and stimulated contractions. In Human Muscle Fatigue: Physiological Mechanisms (Porter R, Whelan J, Eds.). London: Pitman Medical, 1981, pp 130-156. 3. Sahlin K. Intracellular pH and energy metabolism in skeletal muscle of man with special reference to exercise. Actu Physio/ Scund Suppl455: Thesis, Stockholm Sweden, 1978, l-58. 4. Henneman E, Olson CB. Relations between structure and function in the design of skeletal muscles. J Neurophysiol 28:581-598, 1965. 5. Edwards RHT. New techniques for studying human muscle function, metabolism and fatigue. Muscle Nerve 2599-609, 1984. 6. Bigland-Ritchie B, Jones DA, Woods JJ. Excitation frequency and muscle fatigue: Electrical response during human voluntary and stimulated contractions. Exp Neurol 64:414-427, 1979. 7. Buchthal F, Schmalbruch H. Motor unit of mammalian muscle. Physiol Rev 60~90-142, 1980. 8. Saltin B, Gollnick PD. Skeletal muscle adaptability: significance for metabolism and performance. In Handbook of Physiology of Skeletal Muscle (Peachy LD, Adrian RH, Geiger SR, Eds.). Baltimore: Williams, and Wilkins, 1983, pp 551-631. 9. Gollnick PD. Metabolic regulation in skeletal muscle: influence of endurance training as exerted by mitochondrial protein concentration. Actu Physiol Stand uS:53-104, 1986. 10. Reichman H, Pette D. A comparative microphotometric study of succinate dehydrogenase activity levels in type I, IIa and IIb fibres of mammalian and human muscles. Htifochermrtry 74~27-41, 1991. 11. Manning DR, Stull JT. Myosin light chain phosphorylation and phosphorylase activity in rat extensor digitorum longus muscle. Biocbem Biophys Res Commun 90:404-407, 1979.

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FATIGUE

311

12. Close R, Hoh JFY. The after-effects of repetitive stimulation on the isometric twitch contraction of rat fast skeletal muscle. J Physiol (Lond) 197:461-477, 1968. 13. Moore RL, Stull JT. Myosin light chain phosphorylation in fast and slow skeletal muscles in situ. Am J Physiol247rC462-C471, 1984. 14. Klug GA, Botterman BR, Stull JT. The effect of low frequency stimulation on myosin light chain phosphorylation in skeletal muscle. J Biol Chem 257~4688-4690, 1982. 15. Maclaren DPM, Gibson H, Parry-Billings M, Edwards RHT. A review of metabolic and physiological factors in fatigue. Exert Sport Sci Rev 17~29-68, 1989. 16. Atlan G, Beliveau L, Bouissou P. (Eds.). Muscle Fatigue: Biochemical and Physiological Aspects. Masson: Paris, 1991. 17. Maton B. Central nervous changes in fatigue induced by local work. In Muscle Fatigue: Biochemical and Physiological Aspects. (Atlan G, Beliveau L, Bouissou P, Eds.). Mason: Paris, 1991, pp 207-221. 18. Enoka RM, Ranking LL, Joyner MJ, Stuart DG. Fatigue-related changes in neuromuscular excitability of rat hindlimb muscles. Muscle Nerve 11:1123-1132, 1988. 19. Byrd SK, Bode A, Klug GA. Effects of exercise of varying duration on sarcoplasmic reticulum function. J Appl Physiol 104~1383-1389, 1989. 20. Miller RG, Giannini D, Milner-Brown HS, Layzer RB, Koretsky AP, Hooper D, Weiner MW. Effects of fatiguing exercise on high-energy phosphate, force and EMG: Evidence for three phases of recovery. Muscle Nerve 10:810-821, 1987. 21. Edwards RHT, Gibson H. Perspectives in the study of normal and pathological skeletal muscle. In Muscle Fatigue: Biochemical and Physiological Aspects. (Atlan G, Beliveau L, Bouissou P, Eds.). Mason: Paris, 1991, pp 3-15. 22. Kmjevic K, Miledi R. Failure of neuromuscular propagation in rats. J Physiol (Lond) 14O&tO461, 1958. 23. Merton PA. Voluntary strength and fatigue. J Physiol W:553-564, 1954. 24. Cooper RG, Edwards RHT, Gibson H, Stokes MJ. Human muscle fatigue: Frequency dependence of excitation and force generation. J Physiol397:585-599, 1988. 25. Kuei JH, Shadmehr R, Sieck GC. Relative contribution of neurotransmission failure to diaphragm fatigue. J Appl Physiol @3:174-180, 1990. 26. Woods JJ, Furbush F, Bigland-Ritchie B. Evidence for a fatigue-induced reflex inhibition of motoneuron firing rates. J Neorophysiol S&125-137, 1987. 27. Grimby L, Hannerz J, Hedman B. The fatigue and voluntary discharge properties of single motor units in man. J Physiol340:545-554, 1981. 28. Bigland-Ritchie B, Dawson NJ, Johansson RS, Loppold OCJ. Reflex origin for the slowing of motoneurone firing rates in fatigue of human voluntary contractions. J Physiol379:451-459, 1986. 29. Bigland-Ritchie B, Furbursh F, Woods JJ. Neuromuscular transmission and muscle activation in human post-fatigue ischaemia. J Physiol 377:76P, 1986. 30. Liittgau HC. The effect of metabolic inhibitors in the fatigue of the action potential in single muscle fibres. J Physiol (Lond) 178~45-67, 1965. 31. Pagala MKD, Namba T, Grob D. Failure of neuromuscular transmission and contractility during muscle fatigue. Muscle Nerve 7~454-464, 1984. 32. Blomstrand E, Celsing F, Newsholme EA. Changes in plasma concentration of aromatic and branched-chain amino acids during sustained exercise in man and their possible role in fatigue. Acta Physiol Scund l33:115-121, 1988. 33. Morgan WP, Pollock ML. Psychological characterization of the elite distance runner. Ann NY Acad

Sci 301:382-403,

1977.

34. Pandolf KB. Advances in the study and application of perceived exertion. Exert Sport Sci Rev 11:118-158, 1983. 35. Sandercock TG, Faulkner JA, Albers JW, Abbrecht PH. Single motor unit and fiber action potentials during fatigue. J Appl Physiol58:1493-1499, 1985. 36. Smith DO. Mechanisms of action potential propagation failure at sites of axon branching in the crayfish. J Physiol (Lond) 301:243-259, 1980.

312

LUCKIN

ET AL.

37. Spira ME, Yarom Y, Pamas I. Modulation of spike frequency by regions of special axonal geometry and by synaptic inputs. J Neurophysiol39:882-899, 1976. 38. Kernel1 D. The limits of firing frequency in cat Iumbosacraf motoneurones possessing different time course of after-hyperpolarization. Actu Phys Stand 65:87-100, 1965. 39. Kernel1 D, Monster AW. Time course and properties of late adaptation in spinal motoneurones of the cat. Exp Brain Res 46~191-196, 1982. 40. Kernel1 D, Monster AW. Motoneurone properties and motor fatigue. Exp Brain Res 46~197-204, 1982. 41. Bigland-Ritchie B, KukuIka CG, Lippold OCJ, Woods JJ. The absence of neuro-muscular transmission failure in sustained maximal voluntary contractions. J Physiol330:265-278, 1982. 42. Kugelberg E, Lindergren B. Transmission and contraction fatigue of rat motor units in relation to succinate dehydrogenase activity of motor unit fibres. J Physiol (Lond) 288:285-300, 1979. 43. Stephens JA, Taylor A. Fatigue of maintained voluntary muscle contraction in man. J Physiol 22&l-18, 1972. 44. Fenn WO, Cobb DM. Electrolyte changes in muscle during activity. Am J PhysiollkW45-356, 1936. 45. Jones DA, Bigland-Ritchie B. Electrical and contractile changes in muscle fatigue. In Biochemistry of Exercise VII (Saltin B, Ed.). Champaign, IL: Human Kinetics, 1986, pp 377-391. 46. Jones DA. Muscle fatigue due to changes beyond the neuromuscular junction. In Human Muscle Fatigue: Physiological Mechanisms (Porter R, Whelan J, Eds.). London: Pitman Medical, 1981, pp 178-192. 47. Bezanilla F, Caputo C, Gonzalez-Serratos H, Venosa RA. Sodium dependence of the inward spread of activation in isolated twitch muscle fibers of the frog. J Physiol (Lond) 223~507-523, 1972. 48. Metzger JM, Fitts RH. Fatigue from high-and-low frequency muscle stimulation: Role of sarcolemma action potentials. Exp Neural 93~320-333, 1986. 49. Sjogaard G. Electrolytes in slow and fast muscle fibers of human at rest and with dynamic exercise. Am J Physiol245zR25-R31, 1983. 50. Fitts R, Balog EM, Thompson LV. Fatigue-induced alterations in contractile function: The role of excitation-contraction coupling. In Muscle Fatigue: Biochemical and Physiological Aspects. (Atlan G, Behveau L, Bouissou P, Eds.). Mason: Paris, 1991, pp 40-48. 51. Howell JN, Snoedowne KW. Inhibition of tetanus tension by elevated extracellular calcium concentration. Am J Physiol24OrC193-3200, 1981. 52. Bianchi CP, Narayan S. Muscle fatigue and the role of transverse tubules. Science 215:295-2%, 1982. 53. Gyorke S, Palade P. Extracellular calcium transients in skeletal muscle of the frog. Biophys J 59~243, 1991. 54. Simonsen E. Physiology of Work Capacity and Fatigue. (Simonsen E, Ed.). Springfield: Thomas, 1971. 55. Donaldson SKB, Hermansen L. Differential direct effects of H’ on Ca”-activated force of skin fibers from the soleus, cardiac, adductor magnus muscle of rabbits. Pflugers Arch 376:55-65, 1978. 56. Hibberd MG, Dantzig JA, Trentham DR, Golkman YE. Phosphate release and force generation in skeletal muscle fibers. Science 228~1317-1319, 1985. 57. Cooke R, Pate E. The effects of ADP and phosphate on the contraction of muscle fibexs.-Biophys J 48:789-798, 1985. 58. Nosek TM, Fender KY, Godt RE. It is diprotonated inorganic phosphate that depresses force in skinned skeletal muscle fibers. Science 2X:191-193, 1987. 59. Cooke R, Franks K, Luciani GB, Pate E. The inhibition of rabbit skeletal muscle contraction by hydrogen ions and phosphate. J Physiol (Lond) 395~77-97, 1988. 60. Fabiato A, Fabiato F. Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiac and skeletal muscles. J Physiol (Lond) 276~235-255, 1978. 61. Fletcher WW, Hopkins, FG. Lactic acid in mammalian muscles. J Physiol 35~247-303, 1970. 62. Hermansen L, Bjom-Osnes J. Blood and muscle pH after maximal exercise in man. J Appl Physiol 32:304-308, 1972.

MUSCLE

FATIGUE

313

63. Karlsson J, Saltin B. Lactate, ATP and CP in working muscles during exhaustive exercise in man. J Appl Physiol29:598-602, 1970. 64. Sahlin KA, Atrestrand A, Brandt R, H&man E. Intracellular pH and bicarbonate concentration in human muscle during recovery from exercise. J Appl Physiof 45:474-W, 1978. 65. Vergara JL, Rappoport SI. Fatigue in frog single muscle fibres. Nature 252~727-728, 1974. 66. Vergara JL, Rappoport SI, Nassar-Gentina V. Fatigue and post-tetanic potentiation in single muscle fibers of the frog. Am J Physiol232:C185-190, 1979. 67. Renaud JM. The effect of lactate on intracellular pH and force recovery of fatigued sartorius muscle of the frog, Rana Pipiens. J Physiol (Land) 416:31-47, 1988. 68. Sahlin K, Harris RC, Nyland B, H&man E. Lactate content and pH in muscle samples obtained after dynamic exercise. @Itigers Arch 367~1433149, 1976. 69. Wilson JR, McCully KK, Mancini DM, Boden B, Chance B. Relationship of muscular fatigue to pH and diprotonated Pi in humans: A 3’P-NMR study. J Appl Physiol64:2333-2339, 1988. 70. Godt RE, Nosek TM. Changes in intracellular milieu with fatigue or hypoxia depress contraction of skinned rabbit skeletal and cardiac muscle. J Physiol 412:155-180, 1989. 71. Dawson MJ, Smith S, Wilke DR. The [H,PO,‘-] may determine cross bridge cycling rate and force production in living fatiguing muscle. Siophys J 49tT61, 1986. 72. Miller RG, Boska MD, Moussavi RS, Carson PJ, Weiner MW. [3’P]Nuclear magnetic resonance studies of high energy phosphates and pH in human muscle fatigue. J Clin Invest 81:1190-1196, 1988. 73. Weiner MW, Moussavi RS, Baker AJ, Boska MD, Miller RG. Constant relationship between force, phosphate concentration, and pH in muscles with differential fatiguability. Neurology 40~1888-1893, 1990. 74. Cady EB, Jones DA, Lynn J, Newham DJ. Changes in force and intracellular metabolites during fatigue of human skeletal muscle. J Physiol 418:311-325, 1989. 75. Adams GR, Fisher MJ, Meyer RA. Hypercapnic acidosis and increased H,PO, concentration do not decrease force in cat skeletal muscle. Am J Physiol 26OrC805-C812, 1991. 76. Nakamura Y, Schwartz A. The influence of hydrogen ion concentration on calcium binding and release by skeletal muscle sarcoplasmic reticulum. J Gen Physiof 5%22-32, 1972. 77. Klug GA, Tibbitts GF. The effect of activity of calcium mediated events in striated muscle. Exert Sport Sci Rev 16~1-59, 1988. 78. Renaud JM, Mainwood GW. The effects of pH on the kinetics of fatigue and recovery in frog sartorius muscle. Can J Phsyiol Pharmacol63:1435-1443, 1985. 79. Meyer RA, Kushmerick MJ, Dillon PF. Different effects of decreased intracellular pH on concentration in fast versus slow-twitch muscle. Med Sci Sports Exert 15:140, 1983. 80. Renaud JM, Allard Y, Mainwood GW. Is the change in intracellular pH during fatigue large enough to be the main cause of fatigue? Can J Physiol Pharmacol64:764-767, 1986. 81. Takata S, Takai H, Ikata T, Miura I. Observation of fatigue unrelated to gross-energy reserve of skeletal muscle during tetanic contraction-an application of “P-MRS-. Biochem Biophys Res Commun 15’7~225-231, 1985. 82. Le Rumeur E, Le Moyec L, Toulouse P, Le Bars R, de Certaines JD. Muscle fatigue unrelated to phosphocreatine and pH: An “in-viva” ” -P NMR spectroscopy study. Muscle Nerve l&438444,199O. 83. Vollestad NK, Sejersted OM. Biochemical correlates of fatigue. Eur J Appl Physiol57:336-347, 1988. 84. Lewis SF, Haller RG. Fatigue in skeletal muscle disorders In Muscle Fatigue: Biochemical and Physiological Aspects. (Atlan G, Believeau L, Bouissou P, Eds.). Mason: Paris, 1991, pp 119134. 85. Karlsson J, Saltin B. Diet, muscle glycogen and endurance performance. J Appl Physiol31:203206, 1971. 86. Hultman E. Studies on muscle metabolism of glycogen and active phosphate in man with special reference to exercise and diet. Stand J Clin Lab Invest 19r-63, 1967. 87. Banister EW, Tomanek RJ, Cvorkov N. Ultrastructural modifications in rat heart: Responses to exercise and training. Am J Physiol220:1935-1940, 1971.

314

LUCKIN

ET AL.

88. Gollnick PD, King DW. Effect of exercise and training on mitochondria of rat skeletal muscle. Am J Physiol240:15Ct2-1504, 1969. 89. Lagvens RP, Lozada BB, Gomez Dumm CL, Beramendi AR. Effect of acute and exhaustive exercise upon the fine structure of heart mitochondria. Experientiu 22244-246, 1966. 90. Nimmo MA, Snow DH. Time course of ultrastructural changes in skeletal muscle after two types of exercise. J Appl Physiol52:910-913, 1982. 91. Barakat HA, Kasperek GJ, Dohm GL, Tapscott EB, Snider RD. Fatty acid oxidation by liver and muscle preparations of exhaustively exercised rats. Biochem J 288~419-424, 1982. 92. Chen J, Gollnick PD. Effect of hexokinase binding on mitochondria respiration. FASEB J 4:A506, 1988. 93. Dill DA. Applied Physiology. Annu Rev Physiol 1:555-576, 1939. 94. Norman B, Sollevi A, Kaijser L, Jansson E. ATP breakdown products in human skeletal muscle during prolonged exercise to exhaustion. Clin Physiol7:503-509, 1987. 95. Byrd SK, McCutcheon LJ, Hodgson DR, Gollnick PD. Altered sarcopiasmic reticulum function after high-intensity exercise. J Appl Physiol67:2072-2077, 1989. 96. Wilkie DR. Shortage of chemical fuel as a cause of fatigue: Studies by nuclear magnetic resonance and bicycle ergometry. In Human Muscle Fatigue: Physiological Mechanisms (Porter R, Whelan J, Eds.). London: Pitman Medical, 1981, pp 102-119. 97. Taylor DJ, Styles P, Matthews PM, Arnold DA, Gadian DG, Bore P, Radda GK. Energetics of human muscle: Exercise induced ATP depletion. Mugn Res Med 3~44-54, 1986. 98. Dawson MJ, Gadian DG, Wilkie DR. Muscle fatigue investigated by phosphorus nuclear magnetic resonance. Nature 274861-866, 1978. 99. Cooke R, Pate E. The inhibition of muscle contraction by the products of ATP hydrolysis. In Biochemistry of Exercise VII. (Taylor B, Ed.). Champaign, IL: Human Kinetics, 1990. 100. Hermansen L, H&man E, Saltin B. Muscle glycogen during prolonged severe exercise. Actu Physiol

Scund 71:129-139,

1967.

101. Saltin B, Karlsson J. In Muscle Metabolism During Exercise (Pernow B, Saltin B, Eds.). New York: Plenum, 1971, pp 289-299. 102. Green H. How important is endogenous muscle glycogen to fatigue in prolonged exercise? Can J Physiol Pharmucol61:290-297, 1991. 103. Newsholme EA, Leach AR. Biochemistry for the Medical Sciences. New York: Wiley, 1983. Muscle glycogen utilization during work of different intensities. 104. Broberg S, Sahlin K. Adenine nucleotide degradation in human skeletal muscle during prolonged exercise. J Appl Physiol67:118-122, 1989. 105. Christensen EH, Hansen 0. Arbeitsfahigkeit und ehmahrung. Skund Arch Physiol81:400, 1939. 106. Ahlborg B, Bergstrom .I, Brohult J, Ekelund LG, Hultman F, Maschio G. Human muscle glycogen content and capacity for prolonged exercise after different diets. Forsvursmedicin 3:8589, 1967. 107. 108.

109. 110. 111.

GaIbo H, Hoist JJ, Christensen NJ. The effects of different diets and of insulin on the hormonal response to prolonged exercise. Actu Physiol Scund 149~19-32, 1979. Green I-II, Patla A, Jones S, Ball-Burnett M. Fatigue and carbohydrate availability: Central or peripheral effect. Med Sci Sports Exert 19:596, 1987. Pemow B, Saltin B. Availability of substrates and capacity for prolonged heavy exercise in man. J Appl Physiol31:440-422, 1971. Bridges CR Jr, Clark BJ III, Hammonk RL, Stephenson LW, Skeletal muscle bioenergetics during frequency-dependent fatigue. Am J Physiol26OAX43-C651, 1991. Eberstein A, Sandow A. Fatigue mechanisms in muscle fibers. In The Effect of Use and Disuse in Neuromuscular Function. (Guttman E, Itnik P, Eds.). Amsterdam: Elsevier, 1976, pp 515526.

112. Fitts RH, Holloszy JO. Effect of fatigue and recovery on contractile properties of frog muscle. J Appl

Physiol45:899-902,

1978.

113. Metzger JM, Fitts RH. Fatigue from high and low frequency muscle stimulation: contractile and biochemical alterations. J Appl Physiol62:2075-2082, 1989.

MUSCLE

FATIGUE

315

114. Favero TG, Luckin KA, Klug GA. Effect of prolonged exercise on Ca*+ release from sarcoplasmic reticilum. Physiologkt 33rA121, 1990. 115. Luckin KA, Favero TG, Klug GA. Prolonged exercise induces structural changes in SR Ca’+ATPase of rat muscle. B&hem Med Metabol Biof, in press, 1991. 116. Belcastro AN, Rossiter M, Low MP, Sopper MM. Calcium activation of sarcoplasmic reticulum ATPase following strenuous activity. Can J Physiol Pharmocol59:1214-1218, 1981. 117. Bonner HW, Leslie SW, Combs AB, Tate CA. Effects of exercise training and exhaustion on 45C uptake by rat skeletal muscle mitochondria and sarcoplasmic reticulum. Res Commun Chem Path01 Pharmocol14:767-770, 1976. 118. Fitts RH, Kim DH, Witzmann FA. The effects of prolonged activity on the sarcoplasmic reticulum and myofibrils of fast and slow skeletal muscle. Physiologist 2238, 1979. 119. Sembrowich WL, Gollnick PD. Calcium uptake by heart and skeletal muscle sarcoplasmic reticulum from exercise rats. Med Sci Sports Exert 91:64, 1979. 120. Allen DG, Lee JA, Westerblad H. Intracellular calcium and tension during fatigue in isolated single muscle fibers from Xenopus luevis. J Physiof (Land) 415:433-458, 1989. 121. Lannergren J, Westerblad H. Maximum tension and force-velocity properties of fatigued, single Xenopus muscle fibres studied by caffeine and high K+. J Physiol (Land) 409:473-490, 1989. 122. Leberer E, Hartner KT, Pette D. Reversible inhibition of sarcoplasmic reticulum Ca-ATPase by altered neuromuscular activity in rabbit fast-twitch muscle. Eur J Biochem 402:555-561, 1987. 123. Inesi G, Hill TL. Calcium and proton dependence of sarcoplasmic reticulum ATPase. Biophys J &271-280, 1983. 124. Ikemoto N, Ronjat M, Meszaros LG. Kinetic analysis of excitation-contraction coupling. J Bioenerg Biomembr 21:247-265, 1989. 125. Westerblad H, Lee JA, Lamb AG, Bosover SR, Allen DG. Spatial gradients of intracellular calcium in skeletal muscle during fatigue. pftigers Arch 415:734-740, 1990. 129. Grabowski W, Lobsiger EA, Lagau HC. The effect of repetitive stimulation at low frequencies upon the electrical and mechanical activity of single muscle fibres. pfliigers Arch 334~222-239, 1972. 130. Nasar-Gentina V, Passonneau JV, Rappoport SI. Fatigue and metabolism of frog muscle fibers during stimulation and in response to caffeine. Am J PhysioZ241:C4OGC406, 1981. 131. Bianchi CP, Shanes AM. Calcium influx in skeletal muscle at rest, during activity and during potassium contracture. J Gen Physiol42:803-815, 1959. 132. Curtis BA. Ca*’ fluxes in single twitch fibers. J Gen Physiol Z&255-267, 1966. 133. Almers W, McClesky WW, Palade PT. Calcium channels in vertebrate skeletal muscle. In Calcium in Biological Systems, (Rubin RP, Weiss GB, Putney JW, Eds.). New York: Plenum, 1975, pp 321-330. 134. Armstrong CM, Benzanilla FM, Horowitz P. Twitches in the presence of ethylene glycol bis(betaaminoethyl ether)-N,N’-tetraacetic acid. Biochim Biophys Acta 269~605-608, 1972. 135. Gonzalez-Serratos HA, Balle-Aquilera R, Lathrop DA, Garcia MC. Slow inward calcium current have no obvious role in muscle excitation-contraction coupling. Nature 298:292-294, 1981. 136. Feldmeyer D, Melzer W, Pohl B, Zollner P. Fast gating kinetics of the slow Ca*+ current in cut skeletal muscle fibres of the frog. J Physiol (Land) 425~347-367, 1990. 137. Garcia J, Avila-Sakar AJ, Stefani E. Repetitive stimulation increases the activation rate of skeletal muscle Ca’+ currents. PjZiigers Arch 440:210-212, 1990. 138. Williams JH. Depression of post-tetanic twitch potentiation by low calcium and calcium channel antagonists. J Appl Physiol69:1093-1097, 1990. 139. Williams JH. Effects of low calcium and calcium antagonists on skeletal muscle staircase and fatigue. Muscle Nerve W:1118-1124, 1990. 140. Williams JH, Ward CW. Dihydropyradine effects on skeletal muscle fatigue. J Physiol (Paris), in press, 1991. 141. Fuchs R, Reddy Y, Briggs FN. The interaction of cations with the calcium-binding site of troponin. Biochim

Biophys

Acta 221:407-409,

1970.

142. Fitts RH, Courtright JB, Kim DH, Witzmann FA. Muscle fatigue with prolonged Contractile and biochemical alterations. Am J Physiol242zC65-C73, 1982.

exercise:

316

LUCKIN

ET AL.

143. Kirsch RF, Rymer WZ. Neural compensation for muscular fatigue: Evidence for significant force regulation in man. J Neurophysiol57:1893-1910, 1987. 144. Hou KJC, Rymer WZ. Neural control of muscle length and tension. In Handbook of Physiology. Motor Control, (Hall, VE, Ed.). Bethesda, MD: Am Physiol Sot, 1981, pp 257-323. 145. Hoffer JA, Andreassen S. Regulation of soleus muscle stiffness in pre-mammillary cats: Intrinsic and reflex components. J Neurophysiol45:267-285, 1981. 146. Ikai M, Steinhous AH. Some factors modifying the expression of human strength. J Appl Physiof 40:157-403, 1961. 147. Segal SS, Faulkner JA, White TP. Skeletal muscle fatigue in vitro is temperature dependent. J Appl Physiol61:1040-1045, 1986. 148. Maier A, Gambke B, Pette D. Degeneration-regeneration as a mechanism contributing to the fast to slow conversion of chronically stimulated fast-twitch rabbit muscle. Cell Tissue Res 244:635643, 1986. 149. Maier A, Gorxa L, Schiaffino S, Pette D. A combined histochemical and immunohistochemical study on the dynamics of fast-to-slow fiber transformation in chronically stimulated rabbit muscle. Cell Tissue Res 254~59-68, 1988.