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` REVIEW / SYNTHESE

A peripheral governor regulates muscle contraction

Brian R. MacIntosh and M. Reza S. Shahi

Abstract: Active skeletal muscles are capable of keeping the global [adenosine triphosphate (ATP)] reasonably constant during exercise, whether it is mild exercise, activating a few motor units, or all-out exercise using a substantial mass of muscle. This could only be accomplished if there were regulatory processes in place not only to replenish ATP as quickly as possible, but also to modulate the rate of ATP use when that rate threatens to exceed the rate of ATP replenishment, a situation that could lead to metabolic catastrophe. This paper proposes that there is a regulatory process or peripheral governor that can modulate activation of muscle to avoid metabolic catastrophe. A peripheral governor, working at the cellular level, should be able to reduce the cellular rate of ATP hydrolysis associated with muscle contraction by attenuating activation. This would necessarily cause something we call peripheral fatigue (i.e., reduced contractile response to a given stimulation). There is no doubt that peripheral fatigue occurs. It has been demonstrated in isolated muscles, in muscles in situ with no central nervous system input, and in intact human subjects performing voluntary exercise with small muscle groups or doing whole-body exercise. The regulation of muscle activation is achieved in at least 3 ways (decreasing membrane excitability, inhibiting Ca2+ release through ryanodine receptors, and decreasing the availability of Ca2+ in the sarcoplasmic reticulum), making this a highly redundant control system. The peripheral governor attenuates cellular activation to reduce the metabolic demand, thereby preserving ATP and the integrity of the cell. Key words: fatigue, exhaustion, performance, pacing, contractile response. Resume : Les muscles squelettiques actifs peuvent garder constante la concentration globale d[ATP] ([adenosine triphos ` phate]) au cours dun exercice physique dintensite legere en sollicitant quelques unites motrices ou au cours dun exercice ` dintensite maximale en activant une importante quantite de masse musculaire. Ce phenomene nest possible quen pre sence dun mecanisme de regulation concu pour refaire le plus rapidement les stocks dATP et pour moduler le taux duti ` lisation de lATP quand la demande surpasse la resynthese, laquelle situation pourrait entraner une defaillance metabolique. Cet article propose la presence dun processus regulateur ou dun pilote en peripherie ayant le pouvoir de moduler lactivation du muscle de facon a eviter la defaillance metabolique. Ce pilote uvrant en peripherie au niveau cellulaire doit etre capable de ralentir le taux dhydrolyse de lATP en diminuant le degre dactivation des fibres musculai res. Cette capacite serait a la base de ce qui est nomme fatigue peripherique, soit une moindre reponse a une meme stimu lation. La fatigue peripherique se manifeste de toute evidence. On la demontre chez des muscles isoles, des muscles in ` situ, sans aucune stimulation du systeme nerveux central et chez des sujets humains intacts sadonnant a des exercices volontaires par lactivation de petits groupes musculaires et par sollicitation de lorganisme en entier. Lactivation des mus cles seffectue au moins de trois facons : en diminuant lexcitabilite membranaire, en inhibant la liberation du Ca2+ du reticulum sarcoplasmique par laction des recepteurs de la ryanodine, en diminuant la disponibilite du Ca2+ dans le reticu` lum sarcoplasmique, ce qui en fait un systeme de controle hautement redondant. Le pilote peripherique attenue lactivation musculaire afin de diminuer le besoin du metabolisme, preservant ainsi les stocks dATP et lintegrite de la cellule. Mots-cles : fatigue, epuisement, performance, gradation, reponse contractile. [Traduit par la Redaction]

Introduction
The duration for which a given power output can be maintained during exercise or time to task failure is limited

by the ability of the subject to resist fatigue. Fatigue is a progressive change in performance capability that is perhaps the most important modification to the neuromuscular system during exercise (Kay et al. 2001).

Received 25 May 2010. Accepted 2 September 2010. Published on the NRC Research Press Web site at apnm.nrc.ca on 9 December 2010. Reposted on the Web site with correction on 31 January 2011. B.R. MacIntosh.1 Faculty of Kinesiology, University of Calgary, Calgary, AB T2N 1N4, Canada. M.R.S. Shahi. Department of Physical Education, University of Yazd, Yazd, Iran.
1Corresponding

author (e-mail: brian@kin.ucalgary.ca).

doi:10.1139/H10-073 Published by NRC Research Press

Appl. Physiol. Nutr. Metab. 36: 111 (2011)

Appl. Physiol. Nutr. Metab. Vol. 36, 2011

There has been a long-standing controversy regarding the causes of the progressive changes we refer to as fatigue. The physiological factors associated with fatigue were originally classified as central and peripheral fatigue. Central fatigue refers to processes within the central nervous system that make activation of the necessary motor units more challenging, which eventually results in a decrease in voluntary recruitment of motor units (Gandevia 2001). This decrease could be perceived as an unwillingness to continue exercise at the required intensity, despite the ability of the muscle(s) to continue the exercise at that intensity. Alternatively, the muscles reach a point where they are no longer capable of generating the force or power required to perform the required task (the classical point of view). Our definition of peripheral muscle fatigue is a response that is less than the expected or anticipated contractile response, for a given stimulation as a consequence of repetitive or sustained contractile activity (MacIntosh and Rassier 2002). If task failure occurs because of peripheral fatigue, then this contractile response has decreased to a level that no longer allows the task to be continued at the required intensity. In central governor model theory, it has been proposed that a central governor regulates pacing strategy and limits the muscular performance of elite athletes (Noakes 2000; Noakes et al. 2001). This theory is based on the notion that feedback from the periphery provides the central governor, the brain, with information about the disturbance to homeostasis, and subsequently limits the intensity of exercise to restrict the disturbance to homeostasis to a tolerable level. There is no consideration in this theory for the traditional concept of peripheral muscle fatigue, the possibility that muscles can diminish their contractile capability, thereby limiting physical performance. Noakes et al. (2005) have indicated that the central governor must prevail; otherwise, why do muscles not develop rigor during exercise of high intensity. . .? We argue that metabolic catastrophe culminating in rigor is avoided by appropriate attenuation of activation in individual muscle cells. This attenuation originates within the skeletal muscles, so we refer to it as the peripheral governor. This paper presents evidence that there is a peripheral governor and then goes on to propose how it works. Confirming the presence of peripheral fatigue is the first step towards understanding and accepting the existence of a peripheral governor, a local control system that regulates the intensity of muscle contraction. This notion that fatigue is a regulated process is in contrast to the traditional idea that fatigue is associated with depletion of resources, accumulation of waste products, and wearing down of contractile function.

sociated with a peripheral governor, it is necessary to review the process of excitationcontraction (EC) coupling. A cursory review of this process is presented below, but more detail can be obtained from recent publications (Dulhunty 2006; MacIntosh et al. 2006). EC coupling and energy use During voluntary exercise, the central nervous system recruits motor units in the appropriate muscles to perform the desired movement. Individual motor units are activated by the generation of action potentials at the motoneuron soma, and these action potentials are propagated along the axon and all branches of the axon to the nerve terminal at each muscle fibre associated with that motor unit. Neuromuscular transmission results in action potential generation and propagation on each muscle fibre membrane. This action potential is propagated along the length of each fibre and into each fibre along the transverse tubule system. Depolarization of the transverse tubules, associated with Na+ entry, is detected by the dihydropyridine receptors (voltage sensors), and interaction between the dihydropyridine receptors and the ryanodine receptors (RyR) leads to release of Ca2+ from the terminal cisternae of the sarcoplasmic reticulum; K+ leaves the cell to repolarize the membrane. The subsequent rise in intracellular [Ca2+] triggers the activation of 2 major adenosine triphosphate (ATP)-requiring proteins: myosin ATPase and Ca2+-ATPase. The myosin ATPase is associated with force and power generation, whereas the Ca2+-ATPase leads to relaxation. Restoration of Na+ and K+ concentration gradients across the muscle membrane requires activity of the Na+K+-ATPase. The 3 enzymes mentioned above (Na+K+-ATPase, Ca2+ATPase, and myosin ATPase) account for most of the ATP use during muscle contraction. Of these 3, myosin ATPase has the highest potential capacity to use ATP, typically accounting for 60% to 70% of total ATP use (Smith et al. 2005). Ca2+-ATPase is assumed to account for most of the remainder, with Na+K+-ATPase accounting for no more than 10% of total ATP use (Homsher 1987; Barclay et al. 2007). A simple mechanism to restrict ATP use would be to limit Ca2+ release in the active muscle cell. This restriction would reduce ATP use by the myosin ATPase and the Ca2+ATPase. To evaluate what the muscles are capable of during voluntary exercise, independent of the central nervous system, it is necessary to stimulate the muscles under study. If the central nervous system is unable or unwilling to activate the muscles, but the muscles are still capable of their full contractile response, then electrically elicited tetanic contractions will be greater than the voluntary contractions. A multitude of carefully controlled laboratory experiments have been conducted in this way (Jones et al. 1979; Bigland-Ritchie et al. 1986a, 1986b), and it can generally be concluded that a well-motivated individual is able to persist with a physical task until the muscles are no longer able to match the target. Peripheral fatigue is real. An example of peripheral fatigue An example of a study evaluating central and peripheral fatigue is presented in Fig. 1. In this study, subjects were asked to contract their quadriceps muscles briefly every 6 s
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Central and peripheral fatigue

When a physical task is continued until it can no longer be sustained (task failure), it could be that the inability to continue is due to failure within the central nervous system (central fatigue, presumably regulated by the central governor) or to progressive failure along the motor axons and muscle fibres involved in the task (peripheral fatigue) until the required contractile response is no longer achievable. To understand how this decreased muscle activation can be as-

MacIntosh and Shahi Fig. 1. Peripheral fatigue during intermittent submaximal voluntary contractions. The horizontal line marks the target force for 6-s isometric contractions at 10-s intervals. At 30-s intervals, a stimulated contraction of 50 Hz (Stim 50 Hz) and a maximal voluntary contraction (Max Vol Force) were obtained. At no time did the stimulated contraction significantly exceed the maximal voluntary contraction. The exercise was terminated when the target could no longer be achieved. (Adapted from Bigland-Ritchie et al. 1986a with permission of Acta. Physiol. Scand., Vol. 128, Suppl. 556, pp. 717722, fig. 3, # 1986 John Wiley and Sons.)

central governor is increasing, not decreasing, the level of activation with each contraction. This necessary recruitment has been documented frequently as increasing electromyogram (EMG) magnitude while force or power remain at the same level (Bigland-Ritchie et al. 1986a; Hautier et al. 2000; Hettinga et al. 2006). The consequence of central governor control would be a decreasing activation of motor units and a decline in performance as well as EMG magnitude. The peripheral governor, then, does not put the organism at risk; it allows the exercise to be continued but it distributes the demand across a greater number of motor units. This can occur only if the central governor is willing to increase the activation that is necessary to continue the task, and apparently this is often the case. The work described above involved only the biceps muscles, so it is unlikely that there was a general disturbance to homeostasis. It could be argued that a central governor would be less concerned with the local disturbance to homeostasis that occurs in these circumstances. However, the intensityduration relationship that exists for small muscle groups also applies to whole-body exercise, and the interpretations of this relationship are the same in both cases. This relationship is now described and the interpretation is presented.

The intensityduration relationship

to reach a target of 50% of maximal voluntary torque (Bigland-Ritchie et al. 1986a). Subjects were asked to perform a maximal voluntary contraction at 30-s intervals. At these intervals, electrical stimulation at 50 Hz was also applied to elicit a contraction without the involvement of the central nervous system. It can be seen in Fig. 1 that the maximal voluntary and electrically elicited contractions decline together, until they fall to the target force (50% of maximal voluntary contraction). Of particular interest, the electrically elicited contractions were no greater than the maximal voluntary contractions at any time during this task. Fatigue under these circumstances is clearly a peripheral phenomenon and the central governor is apparently quite willing to relinquish this control to the muscles. It is also interesting to note that the decline in contractile response starts very early in the exercise. This early fatigue occurs at a time when the subjects are still capable of achieving the target force, when disturbance to homeostasis would not be too great. In fact, Bigland-Ritchie et al. (1986a) reported that there was no detectable change in [ATP] even at exhaustion, and glycogen levels had decreased by less than 50% at this time. There are various measures of [ATP] obtained during fatiguing contractions and, in most cases, the observed decrease is minor (Dawson et al. 1978; Miller et al. 1988; Baker et al. 1994; Allen et al. 2002). There is an important distinction between the consequences of central regulation of physical performance and peripheral regulation. In the case of peripheral regulation, where the decline in performance capacity begins very early in a submaximal task, it becomes necessary to recruit additional motor units, and (or) increase the frequency of firing, to be able to persist with the task at the target force or power. Therefore, while the peripheral fatigue develops, the When a small muscle group is called upon to repeatedly produce a submaximal power output, the endurance time is dictated by the relative magnitude of that power. A high power output can be sustained for only a short period of time, whereas a lower power output can be sustained for a considerable duration. When several trials at different average power outputs are conducted with appropriate rest intervals (Bishop et al. 1998), an intensityduration relationship is obtained. This relationship between intensity of exercise and endurance has been fit with an equation describing a hyperbola (Monod and Scherrer 1965), similar to that illustrated in Fig. 2. There are 2 important features of the hyperbola. The first of these is that the asymptote parallel with the abscissa represents an intensity of exercise that theoretically can be sustained indefinitely. We call this the critical power. The second important feature of the hyperbola is that the area (work) above the horizontal asymptote associated with any point on the curve is a constant: AWC = tlim (P CP), where AWC is anaerobic work capacity, tlim is the endurance time at any power output (P), and CP is critical power. This constant area is illustrated in Fig. 2 by 2 representative rectangles for trials to the limit of endurance at 2 different average power outputs. The hyperbolic intensityduration relationship has been interpreted in terms of metabolic limits (Moritani et al. 1981). The power output at critical power is thought to be the highest intensity that can be sustained exclusively with aerobic metabolism. Although this power output would appear to be sustainable indefinitely, the reality is that it is sustainable for a reasonably long, but discreet, duration. This limitation is usually ignored. This endurance would imply that a constant power output can only be sustained if the rate of use of ATP does not exceed the rate at which ATP
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4 Fig. 2. The intensityduration relationship. The curved line represents the hyperbolic relationship between power output and limit of endurance for cycle ergometry, although the same-shaped relationship exists for exercise with small muscle groups. In this case, the line is the best fit to a series of time trials where subjects were asked to try to generate the greatest amount of work in a given time. The same relationship can be obtained from a series of trials conducted at a constant power output to the limit of endurance (Carnevale and Gaesser 1991). The horizontal line is placed at the asymptote, indicating the critical power. The rectangles (area) represent the constant work above the critical power for 2 trials.

Appl. Physiol. Nutr. Metab. Vol. 36, 2011

Why regulate ATP use?

Considerable research has focused on the regulation of metabolic processes that replenish ATP. Less effort has been made to consider the regulation of processes that use ATP. However, this is not a new idea. Hochachka (1994) has indicated that to regulate cellular ATP concentration, the use of ATP is just as important to control as the rate of replenishment, suggesting that a . . . simultaneous control of both the ATP demand and the ATP supply arms of the ATP bioenergetic cycle. . . is necessary. Others have come to the same conclusion (Favero 1999). The importance of regulating both supply and demand is described below. It is generally recognized that there is a need to limit the disturbance to cellular homeostasis, and we argue that this is done most effectively at the active muscles, where there is potential for severe disruption of homeostasis. Of particular importance is the need to limit the fall in [ATP] and to prevent a substantial increase in temperature. ATP is the common currency of energy in living cells, and absolute depletion is characteristic of cell death (Bernardi et al. 1999). Even a small decline in [ATP], particularly in conjunction with an increase in adenosine diphosphate ([ADP]) can have detrimental cellular effects. The ratio of [ATP] to [ADP] indicates the energy charge, or the magnitude of energy available from the hydrolysis of ATP. A decline in this energy charge can result in impaired processes that rely on energy from ATP. In muscles, this would include molecular motors, ion pumps, signaling processes, and chemical synthetic reactions. Clearly, it is in the best interest of the cell to preserve [ATP] and to prevent increases in [ADP]. Some decrease in [ATP] is inevitable, and severe depletion, although rare, has been reported in conjunction with ische mic contractions (de Haan 1990; Soderlund and Hultman 1990). However, there is a condition that allows runaway activation of muscle cells, and this results in death. This example of the dire consequences associated with the inability to regulate the use of ATP is presented below. Malignant hyperthermia and the consequences of losing regulation of [ATP] A prime example of uncontrolled ATP utilization occurs in a condition referred to as malignant hyperthermia. In the majority of cases, this disease is caused by a mutation of the RyR (Halliday 2003; Benkusky et al. 2004) and is manifest by an uncontrolled release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle in response to a specific trigger (Nelson 2002; Glover et al. 2004). This uncontrolled release results in extreme disturbance to homeostasis and, if allowed to continue unchecked for more than a few minutes, results in death (Louis et al. 2001; Nelson 2001). Fortunately, the conditions that trigger this spontaneous disruption of Ca2+ homeostasis are avoidable, so those with the mutation of the RyR that is associated with the condition can lead a relatively normal life. Clearly, regulation of EC coupling is an exceedingly important process. Principles of regulating supply and demand for ATP A simple regulatory system is illustrated in Fig. 3A and 3B. In this figure, the container represents total ATP. For simplicity, this fixed amount of ATP can be considered as
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can be replenished by aerobic metabolism (Bishop et al. 1998). The anaerobic work capacity apparently represents a fixed amount of work that can be completed with nonaerobic energy (i.e., energy that is used, in excess of the aerobic supply, when the intensity of exercise exceeds the critical power). An important fact associated with the critical power concept is that a muscle is capable of using ATP at a rate that greatly exceeds the maximal rate of aerobic ATP repletion. The obvious interpretation of a fixed anaerobic work capacity is that there is a limited amount of nonaerobic energy available, and the limit of endurance above the critical power occurs when this is depleted (Barker et al. 2006). However, there is neither consistent glycogen depletion (Saltin and Karlsson 1972) nor exhaustion of ATP when exercise is terminated in these trials (Dawson et al. 1978; Baker et al. 1994). There must be some factor beyond the supply of energy that is limiting performance. This is where the peripheral governor needs to be considered. The contractile response of a muscle is regulated from within, decreasing the utilization of ATP when the ability to replenish it is challenged. This notion is developed further below. The concepts of critical power and anaerobic work capacity were first derived for small muscle groups (Monod and Scherrer 1965), but these concepts also apply to wholebody exercise (Moritani et al. 1981; Bishop et al. 1998). The importance of this observation is that it supports the idea that at least some of the same factors that limit the performance of small muscle groups appear also to limit whole-body performance. For this reason, laboratory experiments on the contractile properties of isolated muscle have relevance in understanding factors that limit whole-body exercise. We look at examples from this perspective after we consider the question: Why regulate ATP use?

MacIntosh and Shahi Fig. 3. Simple regulatory mechanisms. Two control systems are shown with resting condition in upper diagrams and high rate of metabolic demand in lower diagrams. (A, B) A simple regulatory mechanism can slow the decrease in ATP (in container), but depletion is inevitable; (B) shows consequence of increased ATP use with this control system: depletion. (C, D) A slightly more sophisticated control system decreases use of ATP when the [ATP] is threatened; (D) shows the equilibrium position, where the rate of use of ATP is balanced by the rate of replenishment.

would reduce overall energy requirements, it would not permit regulation of ATP supplydemand within each motor unit. If this was the only mechanism for regulation of ATP use, then individual muscle cells would operate like those in Fig. 3A and 3B. ATP depletion would still be inevitable, but to preserve body homeostasis only a few motor units would be activated to total failure. If the model presented in Fig. 3C and 3D is the preferred regulatory process, then it would be expected that the contractile response of isolated muscle would be regulated to a level such that aerobic metabolism would be sufficient to maintain a constant [ATP]. There are several examples in the research literature indicating that this is the case, but we now focus on some recent work that illustrates this idea.

Further evidence for a peripheral governor

Animal experiments The rat medial gastrocnemius muscle, isolated in situ, has been used extensively to investigate the contractile properties of a muscle while maintaining an intact innervation and circulation. Intermittent stimulation of this muscle via the motor nerve results in a transient activity-dependent potentiation followed by a decrease in contractile response (MacNaughton and MacIntosh 2007). The active force decreases to a relatively constant level after 1 or 2 min. If this constant active force represents the active force that can be sustained by aerobic metabolism, then the initial length, and therefore the initial force and corresponding energy requirement, should not affect the final force and corresponding energy requirement. Figure 4 illustrates an experiment in which 2 groups of muscles were stimulated at 1 contraction per second for 5 min, with 1 group at a relatively long length and the other group at a short length. Initial active force was substantially lower at the short length. There are clear differences between these conditions during the first minute, but after this time, both reach a steady active force that is not significantly different. According to our proposal, this should be the force that can be sustained by aerobic metabolism. A third group of muscles in this study was activated half as often at the long length. The active force reached a constant level that is about double that of the other 2 groups. Assuming that energy use is proportional to active force (Awan and Goldspink 1972; Gladden et al. 1978), it seems reasonable to conclude that activation in these muscles is regulated to a level that can be sustained with aerobic metabolism. Recovery Before we leave the isolated muscle experiments, there is another important observation that requires attention. If Ca2+ release is regulated in response to challenges to ATP supply, it would be expected that when exercise is terminated, ATP supply would be restored quickly, and if Ca2+ release was regulated directly, release would rebound towards the control level. This is consistent with closing the lower spout in Fig. 3 and allowing the flow from the upper source to refill the container. It can be seen in Fig. 4 that in these experiments there is a very rapid partial recovery of active force with 30 s of rest. The fact that this recovery is incomplete suggests that there is more than 1 regulatory mechanism at
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representing the total ATP available from nonaerobic sources. The lower spout can be opened to increase the use of, or demand for, ATP, as with activation of contraction, and the upper spout can be opened to replenish ATP. This upper spout represents the aerobic replenishment of ATP. As the level of ATP falls in the container, the float falls and the rate of ATP supply is increased by the consequent opening of the upper spout. However, the capacity to use ATP (size of lower spout) is greater than the capacity to replenish ATP with aerobic metabolism (size of upper spout), and if this situation is permitted to continue, then ATP depletion is inevitable (Fig. 3B). The reality is that ATP depletion does not typically occur. Such depletion can only be avoided if the use of ATP is regulated, as shown in Fig. 3C and 3D. In this figure, as ATP is used, the fall of the float not only increases replenishment, but also attenuates the rate of ATP use, preventing further depletion. The float will fall to the position where ATP use (output through lower spout) is balanced by ATP replenishment (input through upper spout) by aerobic metabolism. It seems logical that each muscle cell has regulatory mechanisms to restrict the use of ATP in a similar way. Obviously, one way to reduce activation of muscles is to consciously reduce the intensity of exercise. This would be the central governor approach. Although this approach

6 Fig. 4. Active force (mean SE) during 5-min repetitive contractions and early recovery. These results show the time course of active force change during repetitive stimulation of the rat medial gastrocnemius muscle. When contractions were 1s1, active force decreased to about 1.5 N, whether length was short or long (RL). There was no significant difference between groups when contractions were 1 Hz. When contraction frequency was 0.5 Hz, active force decreased to double that value. Repetitive stimulation was stopped at 5 min, and 1 contraction was obtained 30 s later. Clearly, there was a rapid recovery of force during these 30 s, particularly when fatigue was the greatest (1 Hz at RL). (Adapted with kind permission from Springer Science and Business Media: MacNaughton and MacIntosh 2007, Pflugers Arch., Vol. 445, p. 362, # 2007 SpringerVerlag.)

Appl. Physiol. Nutr. Metab. Vol. 36, 2011

A proposal that there is a peripheral governor

Clearly, it makes sense that there is a peripheral governor. Each muscle cell should have the capacity to regulate its own activation to limit the rate of ATP use, thereby avoiding catastrophic depletion of this important resource. It has been known for quite some time that repetitive activation of a muscle results in attenuation of EC coupling. Eberstein and Sandow (1963) first suggested this in 1963. More recently, there have been several direct measurements indicating that decreased Ca2+ release is a consequence of repetitive stimulation of a single muscle cell (Allen et al. 1989, 1992, 2008a). Also, in fatigue of whole mammalian muscle, the energy cost per contraction decreases in proportion to the decrease in active force (Gladden et al. 1978). This relationship extrapolates back to zero (no energy cost if no force is generated). If the Ca2+ release was maintained in fatigue, the relationship should extrapolate back to the energy cost for activation (predominantly for Ca2+ uptake). Likely candidates for the peripheral governor Attenuation of Ca2+ release could be achieved by regulatory mechanisms associated with any of several sites along the path of EC coupling described above, but we focus on 3 likely candidates: muscle membrane depolarization, RyR inhibition, and decreased Ca2+ availability. There is strong scientific support for the involvement of each of these in down-regulating the contractile response during repetitive contractions. It should be kept in mind that other sites may also be involved in a highly redundant regulatory process. Membrane depolarization It is a well-known fact that plasma potassium concentration increases during exercise (Lindinger et al. 1995; Medb and Sejersted 1990; Sejersted and Sjgaard 2000) and it is generally accepted that this K+ comes from the active muscles, causing a corresponding decrease in intracellular [K+]. Certainly, decreased cellular [K+] has been reported for repetitively stimulated muscle (Lindinger et al. 2001). The consequence of increased extracellular [K+] and decreased intracellular [K+] is that the equilibrium potential for K+ becomes less polarized and the resting membrane potential tends to follow. When this depolarization becomes extreme, excitability is lost because of inactivation of the Na+ channels. This loss of excitability occurs when the membrane fails to repolarize to about 50 mV. Propagation of the action potential may be impaired before complete loss of excitability occurs (Cairns et al. 1997). It has been demonstrated that Cl conductance is regulated (Pedersen et al. 2005) in circumstances when K+ is accumulating in the extracellular spaces. Chloride conductance is high in the resting state, but is inhibited by acidosis. This inhibition allows preservation of action potential amplitude, in spite of the inhibition of fast Na+ channels. However, later in a period of stimulation, Cl conductance increases and this diminishes action potential amplitude, impairing activation of muscle (Pedersen et al. 2009). Furthermore, it has also been proposed that a feedback mechanism associated with mitochondrial failure can depolarize the t-tubules in mechanically skinned fibres (Rasmussen et al. 2002). These
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work here, as suggested by several authors (Darques et al. 2003; Enoka and Duchateau 2008; Allen et al. 2008b). That there is a very rapid recovery indicates that measurement of contractile properties some time after voluntary exercise or athletic performance will not reveal the full magnitude of fatigue that was present during the event. This needs to be kept in mind when studies of whole-body exercise find little depression of contractile response after otherwise exhausting exercise. This point was raised by Allen and Westerblad (2010) with respect to the attempt by Marcora and Staiano (2010) to demonstrate a lack of peripheral fatigue after voluntary exercise to exhaustion. Note, however, that there were additional problems with that study (MacIntosh and Fletcher, in press). Although recovery is not often studied with high time resolution, there have been other observations of rapid restoration of activation in fatigued muscles (MacNaughton and MacIntosh 2007; Cheng and Rice 2009), confirming a regulatory process with high temporal resolution. There is additional evidence that [ATP] has some regulatory control of Ca2+ release in muscle fibres. Photolytic release of ATP in a fatigued mouse muscle fibre results in enhanced Ca2+ release and a stronger contraction (Allen et al. 1997). This observation supports the notion that [ATP], in the physiological range, participates in regulation of Ca2+ release and could impact the rapid recovery of force when repetitive activation is stopped.

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7 Fig. 5. Ryanodine receptor embedded in sarcoplasmic reticulum membrane. Ion binding sites represent potential regulatory sites for controlling the open and closed state of the channel. Locations are not necessarily realistic but are meant to represent multiple binding sites. FKBP12, FK binding protein 12; PKA, protein kinase A; CaMKII, calmodulin kinase II; Pi, inorganic phosphate; SH-, sulfhydryl groups. (Adapted from Dulhunty (2006) and Wagenknecht et al. (1997).)

mechanisms decreasing excitability of the muscle are consistent with the proposed model for regulation of ATP demand (Fig. 3C and 3D). Although it is generally known that there is a rundown of the K+ concentration gradient across the muscle membrane, it is perhaps not as well known that this rundown is very likely a regulated process. The loss of K+ from the cell is not due exclusively to an inability of the Na+K+ pump to compensate for the ion exchange associated with action potentials. There is a generous distribution of ATP-sensitive K+ channels (KATP channels) in the plasmalemma of skeletal muscles (Spruce et al. 1985). These channels are inhibited (closed) by ATP at the normal resting concentration. However, in the presence of acidosis, a small decrease in [ATP] will result in activation of the KATP channels (Davies et al. 1992). Activation of the KATP channels will accelerate the loss of K+ and hence contribute to depolarization of the muscle cells. The increased K+ conductance associated with activation of these channels also causes attenuation of the action potential (Gong et al. 2003), potentially decreasing Ca2+ release within the cell. The KATP channels could be referred to as energy sensors that attenuate activation of the muscle cell when the energy charge is challenged. It has been demonstrated that activation of these channels contributes to active hyperemia and overcoming vasoconstriction by the sympathetic nervous system, demonstrating a normal physiological function for these channels. Inhibition of these channels by glibenclimide prevents or diminishes the vasodilation due to exercise. Renaud (2002) has proposed that activation of these channels is protective, preventing radical reduction in [ATP] by attenuating activation. It has also been shown that prolonged treadmill running by knockout mice lacking the gene for KATP channels leads to muscle injury (Cifelli et al. 2007), confirming the importance of these channels in preserving muscle function. This mechanism for the control of muscle activation is rather extreme. Long before the shape of the action potential changes, as a consequence of altered ion gradients, there are changes in Ca2+ release. These changes in Ca2+ release probably occur by regulation of the RyR, another mechanism of the peripheral governor. RyR regulation The RyR are the Ca2+ channels of the terminal cisternae. These channels are opened by the dihydropyridine receptors in response to depolarization of the transverse tubules during an action potential. Therefore, these channels regulate the release of Ca2+ into the myoplasm, activating muscle contraction. It has been demonstrated that metabolic products can inhibit RyR activation (Favero et al. 1995), and this makes the RyR a potential energy sensor, similar to the KATP channel. RyR are very large proteins with a broad array of regulatory sites. Each RyR has binding sites for Ca2+ Mg2+, H+, ATP, inorganic phosphate (Pi), calmodulin, calmodulin kinase II, and protein kinase A (Dulhunty 2006). In addition, there are specific sites that can be phosphorylated, and sulphydryl groups that are sensitive to redox potential (see Fig. 5). Some of the potential regulatory interactions, including Mg2+, H+, ATP, Ca2+, and calmodulin are discussed briefly below. For a more detailed discussion, see the recent

review by Dulhunty (2006) and another by Zucchi and Ronca-Testoni (1997). Cytoplasmic Ca2+ activates the opening of RyR at mmol concentrations, but inhibits it at mmolL1 concentrations (Meissner 1994). For Ca2+ to directly inhibit channel opening it would therefore require an abnormally high [Ca2+]. However, calmodulin without Ca2+ bound favours opening of the RyR, whereas with Ca2+ bound, calmodulin inhibits opening of the channel (Zucchi and Ronca-Testoni 1997). This combination is the same complex that activates myosin light chain kinase, which is turned on during repeated twitch contractions, causing activity-dependent potentiation (Grange et al. 1993), so this would appear to be a mechanism that would be functional under physiological conditions. It is known that as [ATP] decreases, free [Mg2+] increases (Konishi 1998). Mg2+ has been reported to inhibit RyR opening (Lamb and Stephenson 1991), possibly by binding to the low-affinity Ca2+ binding sites. This mechanism provides a means of inhibiting Ca2+ release when [ATP] has fallen. It is also recognized that ATP in mmolL1 concentrations facilitates opening of the RyR (Laver et al. 2001), but, as indicated above, this is in the physiological range and [ATP] rarely falls to a level that would inhibit opening. There is also the potential for interactions between inhibitory factors, increasing the apparent sensitivity to any given inhibitor. It is clear that interaction between regulatory substances can modify the sensitivity to Ca2+ (Meissner et al. 1997). This effect can be at either the low-affinity sites, decreasing the [Ca2+] needed to inhibit opening, or at the highaffinity Ca2+ binding sites, increasing the concentration needed for opening the channels. Sarcoplasmic reticulum (SR) luminal Ca2+ and Mg2+ concentrations may also interact in regulating the opening of the RyR (Laver et al. 2004) The 2 mechanisms of the peripheral governor described above can be considered feedback control similar to that shown in Fig. 3. Another potential control mechanism is
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8 Fig. 6. Representation of active force of rat gastrocnemius muscle during repetitive 10-Hz stimulation. Two experiments are shown: 1 with caffeine administered after 2 min (black line) and 1 without caffeine (grey line). When caffeine was given, active force increased a small amount before falling dramatically to close to zero. While stimulation continued, active force slowly increased but did not reach the steady level seen in the experiment in which caffeine was not given.

Appl. Physiol. Nutr. Metab. Vol. 36, 2011 Fig. 7. Active force measured during 10-Hz stimulation with and without caffeine. In the control experiment, stimulation was 10 Hz for 5 min and no caffeine was injected. In the second experiment, caffeine was administered intravenously prior to the 10-Hz stimulation. In the final experiment, caffeine was given intravenously at 2 min of 10-Hz stimulation. Active force with caffeine decreased to a value significantly lower than in the other 2 groups when measured at 3 min and it was still significantly lower than in the control at 5 min. (Adapted from MacIntosh and Kupsh 1987 with permission of Muscle Nerve, Vol. 10, p. 720, # 1987 John Wiley and Sons Ltd.)

feedforward control. If the process of activating a muscle cell actually caused subsequent attenuation of activation, then this would be an example of feedforward control. Calcium availability contributes to regulation in this way. Calcium availability The decrease in Ca2+ release that has been observed in fatigued muscle could occur by inhibition of RyR and (or) by decreased availability of Ca2+ at the release sites. A decrease in free [Ca2+] in the terminal cisternae would reduce the concentration gradient from SR to myoplasm. A smaller gradient would result in slower release of Ca2+, even if RyR were not inhibited. However, as mentioned above, SR luminal Ca2+ may also contribute to the regulation of RyR. There are 2 potential mechanisms by which SR Ca2+ availability could be decreased: transfer of Ca2+ to other locations and binding of Ca2+ in the SR. Furthermore, although measurements in amphibian muscle suggest that total Ca2+ in the SR appears not to be changed (Gonzalez-Serratos et al. 1978), this may not be the case in mammalian muscle. The muscle cell has Ca2+ transporters in the sarcolemma and mitochondrial membranes. Although these transporters have a lower capacity than SR Ca2+-ATPase, there is the potential that repetitive activation of a muscle cell could lead to progressive loss of Ca2+ from the cell or translocation to the mitochondria, resulting in decreased availability in the terminal cisternae. It has been shown that Ca2+ accumulates in mitochondria during exhausting exercise (Tate et al. 1978b). Assuming this Ca2+ comes from the SR, this translocation could reduce Ca2+ availability for release (Tate et al. 1978a). The second mechanism by which free [Ca2+] in the terminal cisternae could decrease is as a result of increased myoplasmic [Pi] and the movement of Pi into the sarcoplasmic reticulum. At mmolL1 concentrations of Pi, Ca2+ binds to it reversibly, and this reaction has the capacity to decrease free [Ca2+] (Fryer et al. 1995; Allen and Westerblad 2001). This temporary removal from the pool of available Ca2+ could contribute to the decreased Ca2+ release that has been observed with fatigue. Most of the evidence for decreased availability of Ca2+ is from cellular experiments, and it is important to consider whether this mechanism could operate in a whole muscle under physiological conditions. There is evidence that Ca2+ availability is decreased by repetitive activation in rat skeletal muscle in situ. Several years ago, we were interested in evaluating the effects of caffeine on the contractile response of rested and fatiguing muscle. The situation of interest here is the fatiguing muscle. If caffeine is added (in this case, injected intravenously) after some fatigue has occurred, it is expected that it will facilitate activation-induced RyR opening (Poledna and Morad 1983). If the decreased Ca2+ release is solely a consequence of inhibition of RyR, then Ca2+ would be available and it might be expected that caffeine would enhance active force. However, if Ca2+ was in limited supply, then caffeine might result in a greater decrease in activation by further depleting the available Ca2+. When caffeine was given to an otherwise rested muscle, prior to a period of 5 min of 10-Hz stimulation, there was a potentiation of twitch active force, but the pattern of change in active force during the 10-Hz stimulation was not different from that when caffeine was not given (MacIntosh and Kupsh 1987). However, when caffeine was given after 2 min of stimulation, a remarkable thing happened. There was a very brief and very small increase in active force (a few contractions), followed by a dramatic and persistent dePublished by NRC Research Press

MacIntosh and Shahi

9 Allen, D.G., Lannergren, J., and Westerblad, H. 1997. The role of ATP in the regulation of intracellular Ca2+ release in single fibres of mouse skeletal muscle. J. Physiol. 498(Pt. 3): 587600. PMID:9051572. Allen, D.G., Lannergren, J., and Westerblad, H. 2002. Intracellular ATP measured with luciferin/luciferase in isolated single mouse skeletal muscle fibres. Pflugers Arch. 443(56): 836842. doi:10.1007/s00424-001-0756-y. PMID:11889583. Allen, D.G., Lamb, G.D., and Westerblad, H. 2008a. Impaired calcium release during fatigue. J. Appl. Physiol. 104(1): 296305. doi:10.1152/japplphysiol.00908.2007. PMID:17962573. Allen, D.G., Lamb, G.D., and Westerblad, H. 2008b. Skeletal muscle fatigue: cellular mechanisms. Physiol. Rev. 88(1): 287332. doi:10.1152/physrev.00015.2007. PMID:18195089. Awan, M.Z., and Goldspink, G. 1972. Energetics of the development and maintenance of isometric tension by mammalian fast and slow muscles. J. Mech. Cell Motility, 1(2): 97108. Baker, A.J., Carson, P.J., Miller, R.G., and Weiner, M.W. 1994. Metabolic and nonmetabolic components of fatigue monitored with 31P-NMR. Muscle Nerve, 17(9): 10021009. doi:10.1002/ mus.880170907. PMID:8065387. Barclay, C.J., Woledge, R.C., and Curtin, N.A. 2007. Energy turnover for Ca2+ cycling in skeletal muscle. J. Muscle Res. Cell Motil. 28(45): 259274. doi:10.1007/s10974-007-9116-7. PMID:17882515. Barker, T., Poole, D.C., Noble, M.L., and Barstow, T.J. 2006. Human critical power-oxygen uptake relationship at different pedalling frequencies. Exp. Physiol. 91(3): 621632. doi:10.1113/ expphysiol.2005.032789. PMID:16527863. Benkusky, N.A., Farrell, E.F., and Valdivia, H.H. 2004. Ryanodine receptor channelopathies. Biochem. Biophys. Res. Commun. 322(4): 12801285. doi:10.1016/j.bbrc.2004.08.033. PMID: 15336975. Bernardi, M., Felici, F., Marchetti, M., Montellanico, F., Piacentini, M.F., and Solomonow, M. 1999. Force generation performance and motor unit recruitment strategy in muscles of contralateral limbs. J. Electromyogr. Kinesiol. 9(2): 121130. doi:10.1016/ S1050-6411(98)00043-1. PMID:10098712. Bigland-Ritchie, B., Cafarelli, E., and Vllestad, N.K. 1986a. Fatigue of submaximal static contractions. Acta Physiol. Scand. 128(Suppl. 556): 137148. PMID:3471051. Bigland-Ritchie, B., Furbush, F., and Woods, J.J. 1986b. Fatigue of intermittent submaximal voluntary contractions: central and peripheral factors. J. Appl. Physiol. 61(2): 421429. PMID: 3745035. Bishop, D., Jenkins, D.G., and Howard, A. 1998. The critical power function is dependent on the duration of the predictive exercise tests chosen. Int. J. Sports Med. 19(2): 125129. doi:10.1055/s-2007-971894. PMID:9562222. Cairns, S.P., Hing, W.A., Slack, J.R., Mills, R.G., and Loiselle, D.S. 1997. Different effects of raised [K+]o on membrane potential and contraction in mouse fast- and slow-twitch muscle. Am. J. Physiol. Cell Physiol. 273(2 Pt. 1): C598C611. PMID: 9277357. Carnevale, T.J., and Gaesser, G.A. 1991. Effects of pedaling speed on the power-duration relationship for high-intensity exercise. Med. Sci. Sports Exerc. 23(2): 242246. PMID:2017022. Cheng, A.J., and Rice, C.L. 2009. Isometric torque and shortening velocity following fatigue and recovery of different voluntary tasks in the dorsiflexors. Appl. Physiol. Nutr. Metab. 34(5): 866874. doi:10.1139/H09-085. PMID:19935848. Cifelli, C., Bourassa, F., Gariepy, L., Banas, K., Benkhalti, M., and Renaud, J.M. 2007. KATP channel deficiency in mouse flexor digitorum brevis causes fibre damage and impairs Ca2+ release
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crease, as shown in Fig. 6. Figure 7 shows the mean values for active force when caffeine was given at 2 min. This experiment can be interpreted to indicate that Ca2+ was in short supply in the SR at the 2-min time. Alternatively, the regulation of Ca2+ release by the peripheral governor overreacted to the transient increase in active force, further shutting down the release of Ca2+. However, if this had been the case, one might expect a more rapid reversal as the depressed activation spared ATP utilization.

Conclusions
It is obviously important for survival to have the capability for short bursts of high power output, but this capability has a high metabolic cost that cannot be sustained. It is therefore necessary to have a biological mechanism to suppress the rate of using ATP to prevent depletion of this essential substrate within each muscle cell; the sustainable processes of replenishment do not have the necessary capacity. In this paper, it is proposed that the peripheral governor regulates muscle contraction to limit the decline in [ATP] when replenishment is challenged so as to keep up with demand. This proposal is consistent with the critical power theory and can be invoked for isolated muscles or intact human subjects doing voluntary exercise with small muscle groups or substantially whole-body exercise. The peripheral governor is proposed to operate by several redundant mechanisms, including the following:  Loss of membrane excitability by activation of KATP and CI channels  Decreased Ca2+ release by inhibition of the RyR  Decreased Ca2+ release by degradation of the SR myoplasmic Ca2+ gradient We are calling these and other similar regulatory processes the peripheral governor in order to contrast sharply with the notion of a central governor that theoretically preserves the integrity of muscle by inhibition of motor nerve activation. The idea that muscles can regulate their own activation does not detract from the importance of the central governor. There can still be conscious and subconscious attenuation of motor pathways that are initiated to preserve muscle or body homeostasis. The central governor may interfere with pacing during endurance events, but it is the peripheral governor that has the final say in limiting the use of ATP by muscles.

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