Neurobiology
of muscle fatigue
ROGER M. ENOKA
AND DOUGLAS
G. STUART
Departments
of Physiology and Exercise and Sport Sciences, University of Arizona, Tucson, Arizona 85721
ENOKA, ROGERM., AND DOUGLASG. STUART.Neurobiology of muscle
fatigue. J. Appl. Physiol. 72(5): 1631-1648, 1992.-Muscle
fatigue encompasses a class of acute effects that impair motor performance.
The mechanisms that can produce fatigue involve all elements of the motor system,
from a failure of the formulation
of the descending drive provided by suprasegmental centers to a reduction in the activity of the contractile proteins.
We propose four themes that provide a basis for the systematic evaluation
of the neural and neuromuscular
fatigue mechanisms: 1) task dependency
to identify the conditions that activate the various mechanisms; 2) forcefatigability relationship
to explore the interaction
between the mechanisms
that results in a hyperbolic relationship
between force and endurance time;
3) muscle wisdom to examine the association among a concurrent
decline
in force, relaxation
rate, and motor neuron discharge that results in an
optimization
of force; and 4) sense of effort to determine the role of perceived effort in the impairment
of performance.
On the basis of this perspective with an emphasis on neural mechanisms, we suggest a number of
experiments
to advance our understanding
of the neurobiology
of muscle
fatigue.
task; force-fatigability
relationship;
ONEPROMINENTCHARACTERISTIC oftheneuromuscular
system is its adaptability.
When it is subjected to a
chronic stimulus, such as immobilization,
training, or aging, it can adapt to the altered demands of usage. These
adaptations can be extensive and have been shown to
affect most aspects of the system, both morphological
and functional. Similarly, the neuromuscular system can
adapt to more acute challenges, such as those associated
with sustained activity. One of the best known acute adaptations is a phenomenon that is referred to as muscle
fatigue (hereafter referred to as fatigue). To advance our
understanding of the adaptive responses that we call fatigue, it is important that we identify a set of principles,
including a definition, that can provide the basis for subsequent studies. However, although the literature on fatigue is extensive, its interpretation
is confounded by the
diversity of definitions and by the variety of paradigms
that have been used to study it. Our perspective is to
consider fatigue as a phenomenon that had its origin in
the study of human performance (for historical precedents see Refs. 5,l7l,l77,l87,190,220).
In this context,
fatigue is a general concept intended to denote an acute
impairment
of performance that includes both an increase in the perceived effort necessary to exert a desired
force and an eventual inability to produce this force (79;
0161-7567/92
$2.00
muscle wisdom;
sense of effort
for other definitions see Refs. 3,16,69,90). Because of its
link to human performance and the multidisciplinary
interest in the study of fatigue, it does not seem appropriate or necessary to attribute more precision to the definition of fatigue. Rather, the study of fatigue should
focus on the mechanisms that can contribute to an acute
impairment
of performance.
Not surprisingly, the notion that the neuromuscular
system can be stressed to the point of exhaustion has
intrigued numerous investigators, particularly in recent
years. From these studies on fatigue have emerged at
least four themes (task dependency, force-fatigability
relationship, muscle wisdom, and sense of effort) that seem
to provide a reasonable basis for future neural and neuromuscular work in this area, especially studies for which
the requisite techniques are already available. Although
many studies have been undertaken in an attempt to
identify a single fatigue factor, there seems to be little
doubt that the concept of fatigue refers to a class of acute
effects that can impair motor performance and not to a
single mechanism that can, under all conditions, account
for the decline in performance. These observations have
led to the notion that the mechanisms underlying fatigue
are task dependent. Furthermore
the fatigue mechanisms appear to cascade so as to exhibit a hyperbolic
Copyright 0 1992 the American Physiological Society
1631
1632
BRIEF
relationship between force and endurance time (force-fatigability relationship)
and to exert interactive effects on
each other. One prominent interaction, which is referred
to as muscle wisdom,
concerns
the parallel changes
(slowin g) in the rate of muscle relaxation and the discharge rate of m .otor neu .rons th at accompa .nies a loss of
force during sustained maximum or strong isometric contractions. Another significant,
but less appreciated, interaction that influences
motor performance
involves
the psychophysical
phenomenon
of the sense of effort
and the force that is exerted during a sustained task.
These issues can provide a conceptual basis for many
studies on muscle fatigue. The purpose of this review is
to describe these four themes (task dependency, forcemuscle wisdom, and sense of effatigability relationship,
fort) and their util .ity as a focus for subsequent studies on
muscle fatigue. A preliminary
account of some of these
themes has appeared previously (213).
Task Dependency
This theme embodies the concept that fatigue is not
the consequence of a single omnipresent
mechanism but,
rather, that it can be induced by a variety of mechanisms.
The term “task dependency”
accounts for the role of the
details of the task in determining the underlying mechanism(s) and sites associated with fatigue. When the details of the task vary significantly,
it appears that the
mechanism s underlyin g fatigue also vary. Furthermore,
for a given task, it seem s that the m echanisms contributing to fatigue can vary as the task proceeds. Task variables that can be manipulated
by an investigator
and
influence the prevailing mechanism include the level of
subject motivation, the neural strategy (pattern of muscle activation and motor command), the intensity
and
duration of the activity, the speed of a contraction,
and
the extent to which the activity is continuously
sustained. These features of the task influence such fatigue
mechanisms
as the central nervous system EN S) drive
to motor neu rons, the muscles and motor u nits that are
activated (neural strategy), neuromuscular
propagation,
excitation-contraction
coupling, the availability of metabolic substrates,
the intracellular
milieu, the contractile
apparatus, and muscle blood flow. The following discussion of the task dependency theme is i.ntended to demonstrate that these diverse mechanisms can, under specific
conditions, induce fatigue; the purpose is neither to provide a comprehensive
review of each topic nor to identify
the boundary conditions associated with various tasks.
Central driue. One popular technique that has been
used to identify the role of various mechanisms in fatigue
has been to compare the force that can be elicited by
supramaximal
electrical stimulation
(imposed activation
by the experimenter)
with the force that the human subject can exert by voluntary activation. This approach typically involves applying single shocks or a brief train of
shocks to the nerve supplying the test muscle to determine w hether the force that is exerted v ,oluntarily can be
supplemented by the imposed stimulation
(76,113). During a 60-s maximum voluntary contraction
(MVC), Bigland-Ritchie
et al. (21,24) found that the force exerted by
the adductor pollicis decreased by -3050%
but that this
decline in force could not be supplemented
by the im-
REVIEW
posed electrical stimulation.
Similarly,
when subjects
performed an intermittent
(6-s contraction,
4-s rest) task
with the quadriceps femoris muscle for which the target
force was 50% MVC, Bigland-Ritchie
et al. (19) found
that the maximal voluntary and electrically elicited force
declined in parallel so that at the endurance limit (mean
time 4.4 min) both the MVC and the electrically elicited
force were equal to the 50% MVC target force. These
observations
suggest that the decline in force (i.e., fatigue) under these conditions was not due to an inability
to provide the necessary motor neuron activation.
However, there appear to be at least four exceptions to
the general notion that humans are able to generate an
adequate central drive during fatiguing activity. First, to
observe a parallel decline in the voluntary
and imposed
electrically elicited force, it is necessary that the subjects
be well motivated and practiced at the task (19,21,22,24,
31,97,110,169).
A lack of motivation or practice presumably results in an inadequate CNS drive to the appropriate motor neurons. Second, it seems that it is difficult,
even in motivated subjects, to maintain a maximal central drive for some muscles, even in an unfatigued state
(69, 76, 124, 176). For example, Belanger and McComas
(6) found that subjects could maximally activate the tibialis anterior, as assessed by the twitch superimposition
test, but that 10 of 17 male and 4 of 11 female subjects
could not maximally activate the plantarflexor
muscles.
This limitation
seems to be enhanced during sustained
activity. When Bigland-Ritchie
et al. (19) had subjects
perform the intermittent
(6-s contraction,
4-s rest) task
to the 50% MVC target force with the soleus, they found
at the endurance limit (mean time 35 min) that the MVC
force had declined to 50% of the initial value but that
imposed electrical stimulation
elicited a force that was
77% of the initial value. Similarly, Thomas et al. (217)
reported
that well-motivated
subjects
had difficulty
maintaining
an MVC for 5 min with the tibialis anterior,
even though the subjects could momentarily
increase the
force with voluntary activation when they were asked to
do so. Despite recent electrophysiological
advances, it
has not been possible to extend the observations
of the
1960s (reviewed in Ref. 186) that revealed a differential
strength of corticospinal
connections
to motor neurons
innervating different muscles. For this reason, in part, it
is unclear why some muscles, and not others, are prone to
this type of failure. Third, subjects appear to have
greater difficulty activating all the motor units innervating a muscle during repeated maximal concentric (shortening) contractions
than during eccentric (lengthening)
contractions
(75, 215, 225). Furthermore,
activation failure appears to vary with contraction
speed and is greatest for low-speed
concentric
contractions
(159a, 180a).
This effect may be due to changes in central drive and
neuromuscular
propagation.
Fourth, during a simulated
4O-day ascent of Mt. Everest in a hypobaric chamber,
some subjects were unable to generate a maximum CNS
drive, as assessed by twitch superimposition,
during a
sustained MVC (104). These observations
on unmotivated subjects, muscle-specific
effects, eccentric contractions, and altitude suggest that fatigue can be caused by
an inability to generate the necessary CNS drive.
Neural strategy. Related to the observation that an in-
BRIEF
adequate CNS drive may contribute to fatigue is the possibility that some tasks may permit a subject to alter the
neural strategy (i.e., muscle activation patterns,
motor
commands)
and hence influence the time course of fatigue (66, 82a, 130, 196). Clearly, changes in the muscle
activation patterns are possible only with tasks that involve submaximal
forces. Such was the case when
Sjergaard et al. (203) had subjects sustain an isometric
knee extensor force at a target of 5% MVC for 1 h. On the
basis of measurements
of intramuscular
pressure and
electromyogram
(EMG) for rectus femoris and vastus
lateralis, they found that the subjects often switched the
activity among the muscles that comprise the quadriceps
femoris group while maintaining the target force for 1 h.
Sjogaard and colleagues (203,204) suggested that the fatigue (12% decline in MVC force and increase in effort)
associated with this task was due to a decrease in muscle
cell excitability that was caused by a loss of K+ from the
cells. It is possible, however, that these effects were minimized by the option the task afforded the subjects to vary
the activity among the quadriceps femoris muscles. Although it has never been examined, the switching of activity during fatigue may occur within parts of a muscle,
because we know that some muscles (e.g., biceps brachii,
biceps femoris, sartorius,
semimembranosus)
consist of
discrete compartments
(219, 228). This seems most
likely in muscles with distributed
attachments,
in which
changes in the direction of the force vector can be associated with changes in motor unit activity (81).
Another, more speculative, example of a change in the
muscle activation pattern is the possible rotation of motor units during fatiguing activity. Motor unit rotation
would provide periods of inactivity that could be used for
the replenishment
of metabolic needs. The concept of
orderly recruitment
implies that once a motor unit has
been recruited it will remain active as long as the force
exerted by the muscle exceeds the threshold force of recruitment
for the unit. Although most investigators
accept this assumption, there were early suggestions that a
muscle could minimize fatigue by rotating some of the
active motor units (85,201). Some evidence of this possibility was provided by Person (184) among the motor
units of rectus femoris during an isometric knee extensor
task. Furthermore,
Enoka et al. (78) examined motor
unit behavior during a ramp-and-hold
task that was performed before and after a fatiguing contraction
and
found that some low-threshold
motor units were not active after the fatiguing activity although the task was
identical to that performed before the fatigue task. This
variation in motor unit recruitment
was interpreted
as
reflecting some degree of history-dependent
flexibility in
recruitment
order among these motor units (see also Ref.
184), which is consistent with the concept of motor unit
rotation. This possibility
adds a new dimension to the
strategies available to the motor system to accommodate
demanding activity.
Associated with the fatigue-related
flexibility in motor
unit behavior (i.e., recruitment
order, discharge rate, and
discharge pattern), there is emerging evidence that the
activation of a motor unit pool may vary with the relative
magnitude of the muscle and load torques. When the
muscle torque is less than the load torque, the active
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1633
muscle lengthens in a so-called eccentric contraction.
Conversely,
when the muscle torque is greater than the
load torque, the active muscle shortens
in what is referred to as a concentric contraction.
It seems that it is
difficult to generate a maximal CNS drive to the motor
unit pool under eccentric conditions, at least in comparison to that achieved in concentric
conditions
(75, 215,
225). Furthermore,
when a contraction
changes from the
shortening
(concentric)
of active muscle to lengthening
(eccentric), there can be a change in the motor units that
contribute
to the muscle force (178). More work is
needed to determine the generality of these observations,
the mechanisms underlying the variability in motor unit
recruitment,
and the susceptibility
of these mechanisms
to the effects of fatigue.
In addition to changes in muscle and motor unit activation patterns,
fatigue-related
changes in the neural
strategy can include alterations
in the motor command.
These changes can affect both the quantity and the quality of the motor command. Clearly, when a subject is
required to sustain a maximal force for a given duration,
the subject does not have the option of increasing the
magnitude of the motor command as the force declines.
In contrast, when the task involves a submaximal
contraction, the subject is able to increase the motor command to counteract the reduction in force due to peripheral (e.g., neuromuscular
propagation,
contractile apparatus) mechanisms.
This strategy
is used frequently
during submaximal fatiguing contractions
and is evident
as an increase in the discharge rate of active motor units
and the recruitment
of additional units (17, 161). The
actual expression
of the increase in motor command,
however, will vary among muscles because of differences
in the upper limit of motor unit recruitment
(144).
Although
much less is known about the qualitative
features of a motor command, it does appear that relatively minor changes in a task are accompanied by significantly different motor commands. For example, the motor command that elicits a one-legged isometric MVC
(concurrent
knee and hip extension) appears to be different from the command associated with a two-legged
MVC. Rube and Secher (197) examined the fatigability
of subjects during the performance
of one- and twolegged MVCs before and after they completed a 5-wk
training program with either the one- or two-legged task.
The training resulted in a reduction in fatigability, but
the effect was specific to the training task; that is, those
subjects who trained with the two-legged MVC became
less fatigable with this task and not with the one-legged
task. Although both legs were trained with the twolegged task, the subjects were less fatigable only during
the two-legged MVC and not when either leg was activated by itself. This observation
suggests that the motor
command for the two-legged MVC is sufficiently
different from that for the one-legged MVC. Clearly, more
work is needed on this issue to determine the specificity
and adaptability
of motor commands.
Neuromuscular
propagation. In studies that have compared the voluntary
and imposed electrically
elicited
force, the protocol has also often included measurements
to determine whether neuromuscular
propagation failure
is associated with the decline in force. The most common
1634
BRIEF
approach
has been to measure the electrical response in
-the muscle (M wave) to the imposed electrical stimu lation. The M w‘ave consi sts of the synchronous sum of
many muscle fiber action potentials th at are elicited by
the electrical stimulation.
Because the M waves are always initi .ated by action potentials tha t begin in the motor axons at the I.evel of mixed nerves or muscle nerves,
changes in the M wave indicate alterations in neuromuscular propagation between the site of initiation
(nerves)
and the site of recording (muscle fibers). Despite the simplicity of this scheme, there remains a controversy over
whether the M wave s change with fatigue. Alth .ough
some studies have reported that M waves do not decrease
during a 60-s MVC (21, 24, 141, 145, 217), others have
shown that the M waves do decrease with sustained activity (8, 158, 175, 209, 232; A. J. Fuglevand, K. Zackowski,
K. Huey, and R. M. Enoka, unpublished observations).
This discrepancy may be partially due to differences in
the tasks performed to induce fatigue. Low-force longduration contractions have been shown to induce greater
M-wave depression than hi gh-force contractions (Fuglevand et al., unpublished observations).
On .e possible explanation for the decline in M waves
could be a reduction in the excitability of the muscle fiber
membranes. This could be accomplished by fatigue-induced accumulation of K+ and depletion of Na+ from the
extracellular spaces. With electrical stimulation
of isolated mouse muscle, Jones and colleagues (132) demonstrated that it is possible to mimic the rapid force decline
with high-frequency
imposed stimulation
by reducing
the Na+ concentration in the bathing medium. Similarly,
muscle action potentials were diminished by increasing
the extracellular
concentration
of K+ (131). Furthermore, Bezanilla et al. (13) demonstrated that manipulation of Na+ in the medium bathing single muscle fibers
could prevent myofibrillar contraction, which they attributed to a failure of action potential propagation in .the
t-tubules. This effect, however, does not seem to be limited to high-frequency conditions, becau se although human subjects can sustain a 5% MVC for 1 h, this is accompanied by an extracellular accumulation of K+ (202) and
fatigue-related
significant increases in EMG amplitude
and decreases in the mean frequency of the EMG power
spectrum (135).
Excitation-contraction coupling. When the task is such
that performance is not impaired by subject motivation,
changes in the neural strategy, or reduction in the M
waves, then the decline in force must be caused by other
mechanisms. Bigland-Ritchie
et al. (17) examined this
condition with intermittent
(6-s contraction, 4-s rest)
submaximal
(30% MVC) isometric contractions of the
quadriceps femoris. During the first 30 min of the task,
the MVC force and electrically elicited force declined in
parallel to 50% of the initial value, yet there were no
significant changes in muscle lactate, ATP, or phosphocreatine and the glycogen depletion was minimal and
confined to the type I and IIa fibers. The decline in MVC
force could not be explained by an inadequate central
drive (M waves), acidosis, or lack of metabolic substrates. However, there was a disproportionate
decrease
in the electrically elicited twitch compared with the tetanic (50-Hz) responses and MVC, which Bigland-Rit-
REVIEW
chic et al. interpreted as evidence of impaired excitationcontraction coupling. On the basis of this rationale, the
decline in MVC force under these conditions was probably caused by a disruption of the link between activation
of the muscle fiber membrane and the force exerted by
the fibers.
Another widely accepted example of excitation-contraction coupling failure involves a standard test of motor unit fatigability (35). In this protocol, isolated single
motor units are activated with 330-ms trains of stimuli
(40 Hz) at a rate of once per second for 2 min (120 trains).
When subjected to this regimen, some motor units [fasttwitch fatiguable (type FF)] fatigue and exhibit a marked
decline in force while other motor units [fast-twitch fatigue resistant and slow-twitch (types FR and S)] do not
fatigue. Although the type FF units can exert little force
after 2 min, the EMG (compound muscle action potential) measured during the test shows little decrease below
initial values (80, 115, 129). Because it has not yet been
shown that 2 min of this stimulation
can deplete the
muscle fibers of metabolic substrates, cause marked alterations in the concentrations of various metabolites, or
impair the contractile machinery, the fatigue is generally
attributed to a mechanism related to excitation-contraction coupling (114, 115, 129).
Although a failure of excitation-contraction
coupling
has also been implicated in other experimental protocols
(62, 65, 73, 129, 174), little is known about the relative
contribution
of the specific mechanisms. In a thorough
review of the possible excitation-contraction
coupling
mechanisms, Fitts and Metzger (84) summarized the
transformation
of an action potential into cross-bridge
activity as involving seven steps: 1) the sarcolemmal action potential, 2) t-tubular charge movement, 3) coupling of t-tubular charge movement with Ca2+ release
from the sarcoplasmic reticulum, 4) Ca2+ release from
the sarcoplasmic reticulum, 5) reuptake of Ca2+ by the
sarcoplasmic reticulum, 6) Ca2+ binding to troponin, and
7) actomyosin hydrolysis of ATP and cross-bridge cycling. Changes in the intracellular
milieu with fatigue
seem to reduce the magnitude of the Ca2’ transient (step
4) (1, 28) and to impair the Ca2+-adenosinetriphosphatase-mediated Ca2+ uptake into the sarcoplasmic reticulum (step 5) (1, 57, 148, 224). The decline in the magnitude of the Ca2+ transient could be due to a decrease in
the t-tubular charge movement (but this is unlikely) (15),
inhibition
of the coupling step, or impairment
of the release process. Some evidence favors the latter mechanism and may involve an increased inactivation
of the
Ca2+ release channel and depletion of Ca2+ stores in the
sarcoplasmic reticulum (28, 84, 222). Furthermore
the
observed decrease in the rate of Ca2+ reuptake into the
sarcoplasmic reticulum may combine with an increased
intracellular
binding of Ca2+ to parvalbumin, troponin C,
and the sarcoplasmic reticulum pump (224) to reduce the
Ca2+ concentration
gradient across the sarcoplasmic reticulum. The net effect of a reduction in the Ca2+ concentration gradient would be to diminish the flux of Ca2+
across the sarcoplasmic reticulum in response to t-tubular charge movement. However, the contribution of these
mechanisms to muscle fatigue in vivo remains to be determined (84).
BRIEF
Despite the uncertainty concerning the relative contributions made by the specific mechanisms to the decline
in force, the process of excitation-contraction
coupling
has been implicated in several reports on fatigue. A common strategy for assessing the impairment
of excitationcontraction coupling has been to monitor the recovery
from fatigue. In these experiments, the force loss due to
impaired excitation-contraction
coupling appears to be
significant, to be most evident after contractions of long
duration, and to recover slowly (30-60 min) (73,146,147,
172). Some evidence suggests that the depression in tetanic force after contractile activity may be due to an
impairment
in the coupling of the t-tubular charge movement to sarcoplasmic release of Ca2+ (222). In comparison, recovery of force loss due to metabolite-induced
impairment of cross-bridge function seems to occur rapidly
(-2 min) (147,174,198), as does recovery from impaired
neuromuscular propagation (4-6 min) (Fuglevand et al.,
unpublished observations; 174). Furthermore the mechanisms underlying the reduction in force appear to depend
on the details of the task and can involve an impairment
of several processes, including excitation-contraction
coupling (Fuglevand et al., unpublished
observations;
147, 174, 188). Experimental
studies are required to define the task-dependent
boundaries that activate the
various mechanisms that cause a reduction in force, including an evaluation of the extent to which they are
activated sequentially.
IMetabolic substrates.
As described by Edwards and
Gibson (71), muscle force will decline when energy demands cannot be met by the rate of supply of ATP and
the metabolites generated by contractile activity (e.g.,
ADP, Pi, H+) influence cross-bridge activity or the supply of energy. Although the decline in force is not always
associated with a depletion of metabolic substrates (17,
202), the extent of the dissociation seems to depend on
the intensity of activity. Hermansen et al. (120) found
that when subjects exercised (cycle ergometer) at a rate
of 70-80% of maximal aerobic power, exhaustion coincided with glycogen depletion in the muscle fibers of lateral quadriceps femoris. In this context, “exhaustion”
represented the point in time when the subjects could not
exert the forces necessary to perform the task. Under
similar conditions, Coyle and colleagues (49,53) reported
that when exercising subjects are fed glucose or have it
infused intravenously,
they are able to exercise longer.
These observations suggest that the availability
of carbohydrates is an important factor in how long motivated
subjects can ride a cycle ergometer at 6585% of maximal
aerobic power (34, 125).
In addition to this task-dependent
reliance on carbohydrates, it seems that the supply of energy can have a
differential effect on the decline in force with continuous
and intermittent
activation of muscle. In these studies,
muscle has been activated with electrical stimulation
for
various durations for the purpose of varying the number
of cycles (activation-relaxation
cycles) within a given
force-time integral. For example, Hultman
and colleagues (11, 45) stimulated the ischemic quadriceps femoris at a frequency of 20 Hz and with an intensity sufficient to elicit a 25% MVC. The stimulation
was either
applied continuously for 52 s or intermittently
(stimula-
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1635
tion-rest durations of 0.8:0.8 s, 1.6:1.6 s, or 3.2:3.2 s) for
~54 s of stimulation.
The decline in force was least for
the continuous stimulation and greatest for the intermittent condition with the most activation-relaxation
cycles
(0.8:0.8 s). Measurements made on biopsies from vastus
lateralis indicated that intermittent
stimulation
was associated with an increase in ATP utilization.
Bergstrom
and Hultman
(11) estimated that -40% of the energy
cost of a l-s tetanus was attributable to the development
and relaxation of force. These results indicate that under
anaerobic conditions the force elicited with continuous
stimulation
is more economical than that produced with
intermittent
stimulation.
However, when the test muscle
(adductor pollicis) was not ischemic, Duchateau and
Hainaut (65) found that the decline in the electrically
elicited (30-Hz) force was similar with continuous and
intermittent
(l-s activation, l-s rest) stimulation.
From
other experiments involving aerobic conditions and the
use of reduced anesthetized animal preparations, there is
evidence of a lower rate of cross-bridge formation during
the steady-state phase of the tetanus than during its rising phase (33,51,153,221).
Therefore it appears that the
energy cost of a task is influenced by whether the exerted
force is intermittent
or continuous and that this effect is
modulated to some extent when the blood flow to the
muscle is occluded.
As a complement to the study of energy supply and its
role in fatigue, many investigators have examined the
effects of the products of ATP hydrolysis on the declin?
in force. One early candidate for a prominent role in fatigue was lactic acid. However, the consensus now appears to be that an elevation of H+ concentration is more
critical than lactate or the undissociated lactic acid (84).
Furthermore, although H+ can inhibit glycolysis, this interaction does not appear to be a major mechanism underlying the decline in force (84). One fruitful approach
to identifying the role of H+ in fatigue has been to reduce
the intracellular
pH in single intact muscle fibers by increasing the CO, in the extracellular medium; the extent
of the reduction in pH (7.0 to 6.6) is similar to that observed in humans during fatiguing contractions (147).
On the basis of such studies, it appears that intracellular
acidification results in a moderate decline in the number
of attached cross bridges and a decrease in the force exerted by each cross bridge (68,147). Qualitatively
similar
observations have been reported in studies on skinned
muscle fibers (44, 50); however, there may be some differences between the two preparations in the magnitude
of the H+-induced decline in force (147).
Edman and Lou (68) suggested that although intracellular acidification is responsible for much of the altered
mechanical performance of muscle with fatigue, the elevated H+ concentration does not provide a complete explanation of the changes. This reservation is based on
the discrepancy in the stiffness of muscle fibers after
intracellular
acidification and fatiguing contractile activity. Probably, the other products of ATP hydrolysis (MgADP and Pi) are able to modulate cross-bridge behavior.
For example, an increase in the concentration
of Pi has
been shown to reduce maximum isometric force but not
to affect the maximum speed of shortening (44,50). Conversely, an increased concentration of Mg-ADP causes a
1636
BRIEF
small increase in maximum isometric force and a modest
decline in the maximum speed of shortening (50). Subsequent studies will undoubtedly
address the interactive
effects of changes in these products.
From these studies on the role of metabolism
in fatigue, it seems reasonable to conclude, as with the other
factors considered with thi s theme, that gi.ven the appropriate conditions an impairment
of metabolism-related
processes can contribute to the decline in force during
fatiguing activity. Furthermore
it appears that factors
related to both the supply of energy and the accumulation of metabolites can contribute to this force reduction.
Summary. When the results from these va riou
. . s paradigms and protocols are consid .ered together, 1t 1s apparent that the decline in force associated with fatigue can
be caused by many different mechanisms.
In fact, it aPpears that it is possible to design an experimental
protocol for which any of the identified mechanisms
can contribute to fatigue. Furthermore
the data suggest that it is
the details of the task that will largely determine the
relative contribution
of the different mechanisms to fatigue. There remains, however, a great deal of work to be
done on this theme to identify the boundary conditions
for each mechanism and to determine whether various
red .uced preparations
appropriately
mi mic the function
of an intact organism. Studies are needed to 1) identify
the association between task variables and fatigue, 2)
characterize the time course and interaction between the
fatigue mechanisms within tasks (Fuglevand et al., unpublished observations;
147,1X,174),
3) assess the generality of the observations
for different motor systems
(e.g., limb, respiratory,
visual, speech), and 4) determine
which mechanisms
are important
in human performance.
Force-Fatigability
Relationship
Although some work has suggested that it is possible to
sustain
low-level
isometric
contractions
indefinitely
(193), most evidence indicates that activation of the neuromuscular
system at any intensity will eventually elicit
fatigue (203,218). The greater the force exerted during a
task, the more rapidly the muscle fatigues (9, 47, 151,
193). Although such a relationship
might be anticipated,
issues about the
it does raise at least two interesting
mechan isms underlyin .g fatigue. First, on the basis of the
rationale associated with task dependency, the observation of a generalized force-fatigability
relationship
suggests that the mechanisms
causing fatigue interact in
such a way that t ‘hey scale with force. The multi-mechanism basis of the task dependen cy observations
suggests
that the force-fatigability
relationship is not a simple exrelationships.
trapolation of motor unit force-fatigability
Second, the tests that characterize motor unit fatigability (35, 107, 199) generally stress one, or perhaps two,
fatigue mechanisms but not the complete set that span
the force-fatigability
relationship.
Studies related to this
theme need to address the role of the various fatigue
mechanisms
in defining the force-fatigability
relationship.
Classical tests of muscle endurance, which involve a
sustained isometric contraction,
have typically revealed
REVIEW
a hyperbolic relationship
between force and endurance
time. For example, when the jaw-closing
muscles sustain
an isometric force at various levels, the associated endurance times are inversely related to the magnitude of the
force (47,48,143).
Similarly, Bellemare and Grassino (9)
found an inverse relationship
between the magnitude of
the transdiaphragmatic
pressure during inspiration
and
the fatigue time constant (i.e., endurance time). Furthermore, when the duty cycle was increased (9, l50), which
amounts to an increase in the work performed
or the
force-time integral for isometric contractions,
the rate of
fatigue increased (i.e., a decrease in endurance time). In a
similar vein, when the duty cycle was held constant and
the frequency of imposed stimulation
was varied (15 or
30 Hz), Garland et al. (100) found that there was more
fatigue when the force-time
integral was greater. The
rate of fatigue has also been reported to increase when
the duty cycle was increased (65) or the duration of the
cycle decreased (ll), which suggests that the rate of energy utilization for intermittent
contractions
also influences the decline in force. Such observations
suggest that
the greater the force exerted, work done, or rate of work
performance during a task, the greater the fatigue experience d by the muscle.
relationship
A central feature of the force-fatigability
seems to be its dependence on the absolute force exerted
during the task. McKenzie and Gandevia (168) had subjects perform intermittent
isometric contractions
with
either the elbow flexor or inspiratory
muscles at two different muscle lengths: the optimal length and a shorter
length that reduced the MVC force by 25%. Although the
maximal absolute force was different at the two lengths,
the subjects performed the intermittent
task at the maximum voluntary
force for each length. Fatigability
was
assessed as the decline in peak force after a series of 18
MVCs. Although the inspiratory
muscles were less fatigued at the optimal length (final force: short length =
81% of initial; optimal length = 87%), the elbow flexor
muscles were less fatigued at the shorter length (final
force: short length = 61%; optimal length = 55%). Fitch
and McComas (82) similarly found a greater fatigability
(decline in electrically elicited torque) for tibialis anterior at its optimum length. These observations
indicate
for the limb muscles that although the relative force was
the same at each length (i.e., for an MVC) and the muscles exhibited different amounts of fatigability, the absolute force was different and fatigability varied in direct
proportion
to the absolute force, as predicted by the
force-fatigability
relationship.
Although
the force-fatigability
relationship
has appeared robust in a variety of experimental
conditions, it
appears that it is possible to alter the relationship
by
varying the rate and pattern of the imposed electrical
stimulation.
Although the rate of muscle activation has
long been known to influence fatigability, it is now apparent that the pattern of activation can also have a significant effect on the decline in force. As expected for the
generalized force-fatigability
relationship,
the rate and
amount of force decline both increase with the frequency
of electrical stimulation,
both for whole muscles (23,132)
and for single motor units (199). This effect presumably
involves a force-dependent
sequential activation of the
BRIEF
mechanisms underlying fatigue (e.g., failure of neuromuscular propagation, excitation-contraction
coupling) (23,
73, 199). However,
when the imposed stimulation
frequency is systematically
reduced, there is less of a decline
in whole muscle force (26, 130, 132). By simply changing
the activation pattern, it is possible to significantly
alter
the force-fatigability
relationship,
so that from the same
initial force there can be different amounts of fatigability. Presumably this effect is the result of a change in the
dominant fatigue mechanism, such as a failure of action
potential propagation
with high-frequency
stimulation
and a failure of excitation-contraction
coupling with lowfrequency stimulation. The frequency-dependent
change
in the fatigue mechanism results in a change in the forcefrequency relationship
with fatigue, such as a decline in
the force elicited with low but not high frequencies
of
stimulation
(52, 73, 129, 199).
In addition to these whole muscle experiments,
a pattern effect has been demonstrated
at the level of the motor unit with only subtle changes in the activation pattern (12). In these experiments,
which are an extension
of work on the catchlike property of single motor units
(36, 206, 231), Stuart and colleagues (12) compared the
fatigability of type FF motor units with two stimulus regimens: one that comprised a constant submaximal
frequency and another that rearranged the stimuli to optimize the force but retain the same average frequency.
Repetitive activation with the optimized stimulus regimen resulted in a greater initial force and less fatigability, which contradicts the expectation based on the generalized force-fatigability
relationship.
It remains to be
shown whether this observation
reflects a change in the
dominant fatigue mechanism or less stress on the prevailing mechanism(s).
Although chronic adaptations
associated with alterations of the normal patterns of usage can change the
fatigability of muscle, there are no systematic studies on
the effects on the force-fatigability
relationship.
While
endurance training is known to decrease fatigability (67,
136), it appears that the muscle atrophy associated with
various reduced-use regimens does not cause the muscle
to become more fatigable, but instead the muscle may
become less fatigable (89, l11,122a, l73,178a, 192,212).
This reciprocal change in force and fatigability is consistent with the force-fatigability
relationship.
However,
the dissociation between changes in maximum force and
fatigability
may be due to the selective impairment
of
high-threshold
fatigable motor units following
a reduced-use protocol (65a). A potentially
informative
experimental strategy would be to characterize
the forcefatigability
relationship
and the time course of changes
in muscles that had undergone various chronic perturbations with the intent of identifying the adaptability of the
various mechanisms that underlie fatigability.
Summary. A generalized force-fatigability
relationship
seems to be valid for most, but not all, experimental
conditions that have been examined. According to this relationship, the greater the force exerted by a muscle, or a
motor unit, during a given task, the more the muscle will
fatigue. Presumably
the mechanisms underlying fatigue
vary with the level of the force that is exerted. Studies are
explore the force-fatigabilneeded that 1) systematically
1637
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300
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1
600
(s1°
rtI
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20
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605045
Stimulus
200
Frequency
40
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35
30
(Hz)
1. Muscle wisdom. A: decline in maximum
voluntary
contraction (MVC)
(less smoot,h line) of adductor
pollicis can be mimicked
by
electrical
stimulation
of muscle (smooth
line) when stimulus
frequency
declined
(from 60 to 20 Hz) over course of task. When stimulus
frequency was held constant,
force declined
more rapidly.
[Adapted
from
Jones et al. (132).] B: submaximal
force elicited in quadriceps
femoris
muscle declined
less when stimulus
frequency
was reduced during the
test. l , Force elicited with variable-frequency
stimulation;
0, force due
to constant-frequency
stimulation.
These data indicate
that with variable-frequency
stimulation
it is possible
to mimic fatigue-related
decline in MVC and optimize
submaximal
force. [Adapted
from BinderMacleod
and Guerin
(26).]
FIG.
ity domain for a variety of muscles and tasks to determine the global nature of the relationship, 2) characterize local regions of the force -fatigability domain where
the rel ationihip is nonmonotonic, 3 ) identify the mechanisms that predominate at various levels of force, 4) assess the interactions between the fatigue mechanisms
that produce the hyperbolic relationship between force
and endurance time, and 5) use the force-fatigability relationship as a probe to examine adaptations in the motor system tha t are associated with short-term changes
in the activation pattern and chronic perturbations such
as long-term activation patterns, immobilization, exercise training, and aging.
Muscle Wisdom
As fatigue proceeds in conscious humans during both
MVCs and imposed contractions (electrical stimulation
with a selected pattern), there is a progressive decrease in
the rate of relaxation in whole muscle (21,72,126), single
motor units (35, 64, 107, 188, 216), and single muscle
fibers (1, 147); a reduction in motor neuron discharge
rate and in the frequency of activation necessary to elicit
the maximum force (20,61); and, for a given submaximal
frequency, a greater degree of fusion in the force (110,
132, 158). For example, the original work (Fig. 1A) demonstrated that the decline in force during a 60-s MVC of
adductor pollicis could be mimicked by a reduction in the
stimulus frequency (60 to 20 Hz) used for the electrically
elicited force (132). Furthermore, Binder-Macleod and
colleagues (25,26) showed that the force elicited in quadriceps femoris with imposed variable-frequency (60- to
30-Hz) electrical stimulation . decreased less than that
with a constant-frequency (60-Hz) protocol, which suggests that reduction of the stimulus frequency serves to
optimize the submaximal force (Fig. 1B). Similarly, Botterman and Cope (32) found that to sustain a submaximal force (25% of maximum) it was necessary to reduce
the stimul .ation rate of fast-twitch motor units. This association of a concurrent decline in force, relaxation rate,
and motor neuron discharge rate has been referred to as
1638
BRIEF
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100
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9
60
8
8
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20
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40
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Stimulus
300
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Frequency
20
40
(H Z >
FIG. 2. Muscle
wisdom-associated
shifts
in stimulus
frequencyforce relationship.
A: fatigue results in a leftward
shift of stimulus
frequency-force
relationship
for frog semitendinosus
muscle (0, before
fatigue; a, after fatigue).
Functional
significance
of this adaptation
is
that although
maximum
force declines with fatigue, a submaximal
stimulus frequency
will elicit a greater proportion
of current
(normalized)
maximal
force when relationship
is shifted to the left. [Adapted
from
Fitts et al. (83).] B: stimulus
frequency-force
relationship
is not shifted
to the left for human quadriceps
femoris,
and at some frequencies
of
stimulation
relationship
is shifted
to the right, exhibiting
low-frequency fatigue (Cl, before fatigue; n , after fatigue).
These data represent shift in relationship
when fatigue was induced by electrical
stimulation of quadriceps
femoris.
The same result was found when fatigue
was induced by voluntary
activation
of muscle (27). These data indicate
that effect of fatigue on stimulus
frequency-force
relationship
is unresolved. [Adapted
from Binder-Macleod
and McDermond
(27).]
“muscle wisdom” (157, 158). The functional significance
of muscle wisdom is that it optimizes the force and ensures an economical activation of fatiguing muscle by
the CNS.
The ability to replicate the decline in MVC force by
reducing the stimulus frequency has been hypothesized
to result from a leftward shift of the stimulus frequencyforce relationship (Fig. 2A). The basis of this rationale is
that if the time course of the twitch increases, then the
activation rate can decline and it is still possible to
achieve the same degree of fusion of the twitch responses. Bigland-Ritchie
et al. (21) proposed, albeit on
the basis of limited data (their Fig. 4), that fatigue causes
a leftward shift in the normalized stimulus frequencyforce relationship because of changes in the time course
of the twitch with fatigue. Accordingly, Fitts et al. (83)
reported that the optimal frequency for the frog semitendinosus muscle decreased from 150 to 60 Hz after 5 min
of electrical stimulation
(Fig. 2A). However, other experimental observations on both motor units (199, 216) and
whole muscles (10, 27) showed that the stimulus frequency-force relationship
normalized to the maximum
force does not always move to the left with fatigue (Fig.
2B; see also Ref. 52). Rather, depending on the fatigue
regimen, the relationship may move to the right for some
stimulus frequencies (Fig. 2B).
At the motor unit level, in both conscious humans
(216) and experimental
animals (188), the stimulus frequency-force relationship seems to move in opposite directions as a function of motor unit type. Powers and
Binder (188) found that the stimulus frequency-force relationship for type FR motor units moved to the left immediately after a period of stimulation
and then to the
right after -30 mi n of recovery. In contrast, the sti mulus
frequency-force relationship for type FF motor units simply moved to the right. Because the activation of muscle
is known to influence processes that both potentiate and
diminish force (Fuglevand et al., unpublished observa-
REVIEW
tions; 103, 108, 129, 142, 179, 189), Thomas et al. (216)
make the reasonable suggestion that the differences
among motor units in the shift of the stimulus frequency-force relationship
depend on the balance between the time courses of fatigability
and potentiation
for each unit. Because whole muscle responses represent
the weighted average of the constituent motor unit responses, this variability
among motor units raises the
issue of how various tasks influence the direction of the
shift in the stimulus frequency-force relationship for the
whole muscle.
Most of the evidence on the activation patterns associated with muscle wisdom has been derived from studies
of whole muscle and populations of motor units (18,105).
Largely because of technical limitations,
much less is
known about the contribution
of single motor units to
this phenomenon. Because muscle wisdom has been mimicke d by reducing the stimulus frequency, it was anticipated that evidence of a fatigue-related decline in motor
unit discharge would be forthcoming. Although some investigators (30, 94, 110, 158) reported an expected decline in the discharge rate of single motor units during
maximal and submaximal sustained contractions, others
have observed either no reduction in discharge rate (161)
or a variety of discharge patterns in single motor units,
including an increase in discharge rate (31, 63, 102, 105,
161, 182) during sustained submaximal
contractions.
Consequently, although the net discharge (based on measurements for populations of motor units) appears to decline with sustained activity, there can be substantial
variability at the level of individual motor units.
On the basis of the population responses, therefore, it
seems that the muscle wisdom theme is associated with a
concurrent decline in force, relaxation rate, and motor
neuron discharge rate that optimizes muscle force and
ensures the economical activation of fatiguing muscle by
the CNS. Although the prolongation
of the twitch and
the increased sluggishness of the muscle may be appropriate for isometric conditions, they do not seem optimal
for rhythmic activities, such as locomotion. The slower
relaxation of muscle will increase the energy consumed
by a muscle as it works against antagonist muscles. This
requisite coactivation will increase the energy cost of a
task and will resul t in a decrease in the net torque exerted about a joint for a given leve 1 of muscle activation.
Clearly the muscle wisdom theme needs to be extended
to dynamic conditions to de termine whether the adaptations parallel those observed under isometric conditions.
Sensory feedback hypothesis. In principle, the muscle
wisdom-associated
change in motor neuron discharge
with sustained activation should be mediated by some
combination
of afferent feedback from peripheral
sources, adaptation in the discharge rate of segmental
interneurons
and motor n.eurons, and than ges in descending commands from suprasegmental centers. Seyffarth proposed that “in fatigue the active units usually
decrease in frequency. . . [which] might be due to afferent impulses sent from the fatigued muscle to the spinal
medulla . . . This view appears to be supported by the
results of the ischaemia experiments”
(Ref. 201, p. 46).
Bigland-Ritchie
et al. similarly suggested that “during
fatigue, motoneurone firing rates may be regulated by a
BRIEF
peripheral reflex originating
in response to fatigue-induced changes within the muscle” (Ref. 18, p. 451), which
has been referred to as the sensory feedback hypothesis (213).
Although some indirect evidence has implicated smalldiameter afferents (group III/IV) in the reflex inhibition
of motor neurons during fatigue (99, lOl), the discharge
of many slowly conducting group III/IV
mechanoreceptor afferents declines during the initial phase of fatigue
(117, 118). Alternatively,
because motor units do not exhibit a decline in discharge rate during sustained activity
until recovery from anesthetic block is complete, which
suggests that small-diameter
axons are involved, Bongiovanni and Hagbarth (30) proposed that the decline in
discharge rate from a high initial value depends on disfacilitation (i.e., a reduction in fusimotor-driven
feedback
from muscle spindles; see also Ref. 229). Subsequently,
direct evidence in favor of this possibility was reported by
Macefield et al. (156), who found that the discharge of
most muscle spindle afferents decreased by -50% during sustained submaximal isometric contraction of the
human dorsiflexor muscles. These observations suggest
that the fatigue-related
decline in motor unit discharge
does include a peripheral component (94), but the relative roles and time courses of reflex inhibition mediated
by small-diameter
afferents and disfacilitation
of the
motor neuron pool are unresolved. One possibility is that
“any decline in motoneurone discharge rate during the
first 5-10 s of a maximal voluntary contraction may reflect the reduction in muscle spindle input and increase
in presynaptic inhibition, while metabolic effects exerted
reflexly through small-diameter
afferents contribute
more later in the contraction”
(90).
At present, there are conflicting observations on the
effects of fatigue on the sensitivity of large-diameter proprioceptive afferents and their spinal reflex efficacy. Initial results on the sensitivity of muscle spindle afferents
in anesthetized reduced animals are generally in agreement, with fatigue shown to enhance the responsiveness
of group Ia and II afferents to single motor unit contractions (46, 77, 233; cf. 180). However, evidence from
conscious humans indicates that fatigue results in a decline of fusimotor drive to muscle spindles (30) as well as
other mechanisms that may contribute to a reduction in
spindle discharge during sustained isometric contractions (156). The effects of fatigue on the group Ib tendon
organ afferent are also uncertain. In studies on reduced
animals, there is evidence of little (208) or no (109)
change in tendon organ responsiveness, whereas there
appears to be a reduction in group Ib responsiveness to
whole muscle stretch (128) and a reduction in contraction-induced group Ib autogenic inhibition in motor neurons (233). There is similar uncertainty concerning the
spinal reflex efficacy of this sensory input. Some evidence suggests that fatigue enhances the efficacy of
short- and long-latency reflex EMG and motor neuron
responses to brief muscle perturbations
(55, 139, 227),
but these results appear to be contrary to other reports
(54, 112, 127). Studies are needed that examine the effects of type-identified
motor units on afferent fibers
during fatigue in reduced animals (77) and conscious humans (226); the interactions among proprioceptive feed-
REVIEW
1639
back, recurrent inhibition, and motor neuron adaptation
in experimental animals (229); and analysis of spinal reflex transmission
in interneuronal
pathways in the
conscious human, with use of recently developed techniques (86).
In the formulation
of the sensory feedback hypothesis,
it was also emphasized that “The decline in motoneurone
firing rates seen during fatigue of a sustained m.v.c. may
result primarily
from changes in central motoneurone
excitability; the time course of frequency changes is quite
similar to that reported by Kernel1 and colleagues for
changes in the discharge rates of cat single motoneurones in response to constant current injection” (Ref. 18,
p. 458). Kernel1 and Monster (137, 138) certainly provided convincing evidence that the intracellular
injection
of a sustained depolarizing current elicits, in the presence of an after-hyperpolarization
in the action potential, a progressive reduction in the discharge rate of motor neurons in a deeply anesthetized adult cat. This adaptation, which has been termed late adaptation, is more
prominent in larger motor neurons and, for the same cell,
it is more pronounced at higher initial discharge rates
(137, 183, 205). It is important
to emphasize, however,
that these results were obtained in deeply anesthetized
cats, whereas the sensory feedback hypothesis is based
on the voluntary contractions of humans. It has been
argued that the afterhyerpolarization
and its obligatory
late adaptation are unlikely features of motor neuron
discharge during voluntary contractions (205, 206). On
the basis of these various results, there is a need for substantially more work on discharge rate adaptation and its
association to the sensory feedback hypothesis. The
change in motor neuron discharge during fatigue undoubtedly involves an interaction between intrinsic motor neuron properties and synaptically mediated effects
associated with muscle activation (i.e., as attributable to
descending command signals, interneuronal
pattern generation, and sensory feedback).
Despite the uncertainty of the mechanisms underlying
the change in motor unit discharge during fatigue, they
undoubtedly exert a powerful effect on the activity of the
motor neuron pool. When a human subject sustains a
submaximal force to exhaustion, the whole muscle EMG
increases, yet motor unit discharge appears to decline
(18,102,185). Consequently, the increase in EMG is generally attributed to an increase in the recruitment of motor units. This means that, for a given excitatory drive to
the motor neuron pool during fatigue, there is a dissociation between the recruitment and discharge rate of motor
units. In contrast, increases in muscle force during nonfatigue conditions are accomplished by concurrent increases in motor unit recruitment
and discharge rate
(214). Fatigue-inducing
activity, therefore, must activate
some influential processes, either related to intrinsic motor neuron properties or synaptically mediated effects,
that permit an excitatory drive to recruit motor units yet
for discharge rate to decline. Furthermore, these effects
seem to be capable of influencing nonfatigued synergist
muscles (116).
Although most attention has focused on potential roles
of intrinsic motor neuron properties and synaptically
mediated effects in the decline of motor unit discharge, a
1640
BRIEF
contribution
from a reduction in central drive cannot be
excluded. Formulation
of the sensory feedback hypothesis was based on observations
of a decline in the discharge of motor unit populations in biceps brachii during
sustained MVCs (18, 201, 230). Because the subjects
were highly motivated and practiced at the task and on
tech .nique, it was
the b asis of the twitch superimposition
assumed that central drive was maximal throughout
the
task. Subsequently, Garland and McComas (101) demonstrated a reduction in the excitability
of soleus motor
neurons (H reflex) in response to an imposed (electrical)
intermittent
stimulation
regimen that induced fatigue.
Although this evidence implicates
a peripheral
reflex
mechanis m in the diminution of motor unit discharge, it
does not eliminate a role for a decline in the central drive.
Along these lines, Maton (160) recorded from cells in
area 4 of the motor cortex of monkeys as they exerted
repetitive isometric elbow-flexion
torques (duration 2-10
s). On the basis of spike-triggered
averaging, the cortical
cells were shown to be associated with the EMG of the
muscles th .at cross the elbow joint . Maton examined the
change in cortical cell discharge and the EMG power
spectrum from the 1st to the 20th repetition. As with the
motor unit studies, cortical cell discharge was found to
decrease, remain constant,
or increase as the EMG
power spectrum changed. This suggests that motor neuron discharge may also be modulated by descending signals during fatiguing contractions.
Summary. Although the adaptability of motor unit discharge seems to be well established at the level of whole
muscle, there is less certainty about whether all motor
units contribute to this effect, and the relative significance of the mechanisms
(sensory feedback, spinal neuron adaptations,
descending modulation)
that control
the change in motor unit behavior remains to be determined. Studies are needed to 1) examine the discharge
behavior of single motor units in various fatiguing tasks,
including dynamic conditions, 2) characterize fatigue-related changes in the efficacy of spinal reflex pathways, 3)
quantify
fatigue-induced
changes in the transducing
properties
of various afferent species, 4) determine the
functional Si .gnific ante of spinal neuron adaptation and
its potenti al relati on to m ore pe ripheral mechanisms
of
discharge rate adaptation, and 5) assess the role of descending modulation of motor neuron discharge during
fatiguing activity.
Sense of Effort
Whenever a human subject is asked to sustain a submaximal force for an extended period of time, such as
holding a heavy briefcase while waiting for a bus, the first
hint that this task cannot be accomplished indefinitely is
not an inability to exert the necessary force but, rather, a
perception that it is necessary to increase the effort associated with the task (93, 133, 162, 165, 166). It is even
possible, especially with some clinical conditions, for an
individual to report an effort-related
fatigue but with no
impairment
of the ability to exert force (152, 211). The
effort associated with performing
a task is assessed by
requiring subjects to match forces. It seems that subjects’
judgments are based on the effort required to generate a
REVIEW
force rather than the absolute magnitude of the force
that is exerted. This judgment is referred to as the sense
of effort and is distinct from the force sensation associated with a contraction.
Because increased effort and
force failure are associated with an impairment
of motor
perform ante, th .ey are both regarded as essen tial features of fatigue. Accordingly 9 any physiological
process
that contributes
to either of these features can be described as a fatigue mechanism.
Corollary discharge. Three lines of experimental
evidence suggest that the sense of effort appears to be
strongly influenced, if not totally dependent, on centrally
generated corticofugal motor commands that give rise to
corollary
discharges
(2, 39, 123, 167). Corollary
discharges are defined here as “the internal actions of motor
commands’ ’ (167) and possibly of the high-level neuronal
processing associated with the formulation
of such commands (S. Gandevia, personal
communication;
152).
From this perspective, the sense of effort is a sensation
derived from the component of the corticopetal
component of the coral .lary discharge that projects to the primary somatosensory
cortex.
As reviewed by McCloskey
et al. (167), the evidence for
a role for corollary
discharge in the sense of effort is
based on an analysis of perturbations
to the system at
three different levels of the neuraxis. First, when the
force that a muscle can exert is experimentally
reduced
(e.g., by fatigue, with curarization,
by cutaneous-derived
inhibition of motor neurons, or by their reciprocal inhibition elicited by vibration of the antagonist muscle), the
perceived effort for a task in crea ses in association with
the more substantial
motor corn mand that the su bject
must generate to achieve the target force (42,95,96,164,
166). Second, when the excitability
of a motor neuron
pool is experimentally
heightened (e.g., vibration
of a
muscle to elicit an excitatory
spindle discharge), there
can be a decrease in the necessary motor command and
in the perceived effort (166). Other investigators,
however, reported the converse observation that vibration of
the muscle tendon consistently
increases force sensation
during a muscle contraction
(38, 134), which suggests
that intramuscular
receptor S are able to influence the
perception of muscl .e tension ( 37,39). T hird, intracranial
lesions due to simple motor strokes can result in muscle
weakness
that requires an increase in centrally generated commands to achieve normal activation of spinal
motor neurons. Even when these lesions produce only
motor deficits with no clinically detectable loss of peripheral sensation, there is an increase in perceived effort
(91, 92, 96).
Psychophysical
experiments
have demonstrated
the
independence of perceived effort and force failure during
sustained activity. When subjects were asked to support
a weight with one h.and for 10 min, they were able to do so
but, with a matching contraction
performed by the contralateral
hand, indicated that the perceived effort increased during the task (166). Similar observations
have
been reported for intermittent
(brief rest periods) submaximal and maximal contractions
(39). In these studies, subjects are required to estimate the force during the
fatiguing contraction
with the contralateral
limb, and investigators
infer, on the basis of the increase in the per-
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0
II
0
20
I1
40
60
1
80
100
Excitation
(% maximum)
A:
FIG. 3. Relationship
between
muscle force and perceived
effort.
mean values for 5 subjects and 2 muscles (0, adductor
pollicis; 0, quadriceps femoris).
Perceived
effort increases as an exponential
function
of muscle force. Decreased
steepness of curve indicates
reduced discriminative capability
for sense of effort.
[Adapted
from Banister
(4).] R:
modeling
studies (88, 119) suggested a sigmoidal
relationship
between
excitatory
drive to a motor neuron pool (input) and force (output).
This
comparison
suggests that sense of effort is not a simple linear interpret,ation of excitatory
drive t.o a motor neuron pool.
ceived amplitude of the matching force, that the subjects
were estimating effort. Some studies have found that
during a constant-force task the perceived effort increases as a power function of duration and that for different tasks the perceived effort increases as a power
function of the target force (4, 34a, 91, 167, 177a, 210).
Similarly, when the effort associated with a handgrip contraction was held constant, the decline in force was characterized by an exponential fu nction ML 134a). Others,
however, have found a linear relatio nship between the
matching force and time during constant-force contractions (93, 133, 166).
The shape of the perceived effort-force relationship
(Fig. 3A) implies a reduced discriminative capability for
the perceived effort at low forces. Interestingly, the relationship between perceived effort and force is opposite to
that predicted from modeling studies (88, 119). These
models have produced a sigmoidal relationship between
the excitatory drive to the motor neuron pool and the
force exerted by muscle (Fig. 3B). According to this relationship, the requisite increase in excitatory drive necessary to increase force by 10% is greater at high force
levels. In contrast, the perceived effort increases more
for a 10% increase in force at low forces (Fig. 3A). This
difference suggestsa nonlinear transformation, as can be
achieved with neuronal networks, between the excitatory
drive to a motor neuron pool and perceived effort.
Although the senseof effort appears to be derived from
corollary discharge, this association is probably influenced by humoral factors circulating in the cerebrospinal fluid. This expectation is based on observations of
the effect of various pharmacological agents on endurante capability. For example, the administration of amphetamine increases the time of swimming rats to reach
exha ustion (14). Furthermore the pretreatment of running rats with 6- hydroxydopamine , a neurotoxin that destroys catecholaminergi .C fibers, decreased the time to
reach exhaustion (121). Such observations have led investigators to conclude that epinephrine (122) and the
neurotransmitter
Ei-hydroxy tryptamine
(29, 43) may
1641
play a role in central fatigue. If endurance time is influenced by such agents, then it seems likely that the
sense of effort would also be affected. This possibility
awaits investigation.
Systems issues. Despite the significance of perceived
effort as it relates to fatigue experienced by humans, little is known about the sense of effort and fatigue. There
are at least four avenues that invite systematic investigation at the systems level of inquiry. First, the relationship
between the sense of effort and the magnitude of force
reduction during fatiguing contractions should be quantified for different muscle groups and motor tasks. It is
unclear whether this relationship would be affected by
the motor system (e.g., respiratory vs. jaw vs. limb), muscle mass (hand vs. leg), muscle function (flexors vs. extensors, single joint vs. multi-joint), or degree of direct
cortical control (hand and forearm vs. leg). Furthermore,
because force failure is known to be task dependent, it is
necessary to determine the influence of motor task on
the relationship between the sense of effort and force
reduction. This would involve an evaluation of the effects
of subject motivation, the intensity and duration of the
activity, and the extent to which the activity is continuously sustained.
Second, there is a need to examine the effects of fatigue in experimental paradigms that have been used previously to demonstrate the importance of sensory feedback in seemingly simple low-force tasks: jaw control in
intact and deafferented monkeys (106); postural control
in intact humans after ischemic deafferentation of the
legs (60, 163); and thumb, wrist, and arm movements of
humans with selected sensory neuropathies (159, 195,
200). The relationship of this literature to the perception
of force during fatiguing contractions has not yet been
considered. For example, sensory updating may still be
required for such perceptions, even with the availability
of the sense of effort.
Third, the role of corollary discharge and kinesthesis
has recently been extended to include judgments about
the timing of muscle contractions (167) and the control
of fine manipulation (98). The perception that is formed
is presumably task dependent; it could be critical in tasks
that require the cooperative activation of separate muscle groups for high-speed movements in which sensory
feedback is not available to the control system. Studies
on the effect of fatigue on timing judgments could provide insight into both the types of motor performance
most sensitive to the adaptations that underlie fatigue
and the mechanisms by which corollary discharge may
mediate this perception. The implication of a role for
corollary discharge in fine manipulative tasks (98) underscores the precision of perceptions based on corollary
discharge. Indeed, Gandevia and Rothwell were able to
conclude that “motor commands can be precisely monitored and fractionated for individual intrinsic muscles of
the human hand without recourse to afferent feedback”
(Ref. 98, p. 1117). It would be of interest to determine
whether this discriminative capability was impaired by
fatigue.
Finally, virtually no information is available on the
relationship between the sense of effort and the readiness potential (Bereitschaftspotential)
(140), which is a
1642
BRIEF REVIEW
negative-going signal that is averaged from scalp electroresonance have all contributed to recent advan ces in our
encephalogram
recordings and thought to originate in understan ding of the mechani sm s underlying clinically
cerebral cortical structures during the planning of volunrelevant fatigue. These mechan sms include adaptations
tary (particularly novel) movement. However, a prelimiin neuro muscular transmission
muscle membrane excitation, excitation-contraction
coupling, intracellular metnary report has shown that muscle fatigue is accompanied by an increased readiness potential, suggesting that
abolic changes, and substrate depletion (70, 149, 176,
“isometric hand contractions with fatigued muscles in- 181,194). For the role of CNS pathophysiology
in fatigue,
however, progress has been far slower due to problems of
volve a greater degree of cortical activation or in other
terms, the engagement must be higher when working
definition, inattention
to the potential value of psychophysical tests, and lack of control data (56). Nonetheless,
with fatigued muscles” (87). An extension of this finding
might lead to establishing electrophysiological
markers
well-established techniques that are now in regular cliniof suprasegmental
factors in fatigue. For example, it cal use (74, 176) can be used to study suprasegmental
would be valuable to determine whether fatigue has a aspects of clinical fatigue. For example, Stokes, Edwards
greater effect on the early bilateral component of the and colleagues (211) used these techniques to examine
readiness potential than on the later unilateral compopatients with “effort syndromes,” a term loosely used to
describe a variety of syndromes that include an increased
nent. This would be of interest, because the early component has recently been shown to be primarily generated
sense of effort during activities of daily living. Their paby the supplementary
motor area and the latter by the tient sample was shown to have central, rather than peprimary motor area (58). This assessment was based the ripheral, neuromuscular
impairments.
Similarly, in paconcurrent measurement of the readiness potential, the tients suffering from the “chronic fatigue syndrome,”
and regional blood flow. there is recent eviden .ce that the abnorma .lity was exmagnetoelectroencephalogram,
pressed 66above the level of the motor cortex” and “the
could potentially
This combination
of measurements
provide a noninvasive method of determining the role of executiv ‘e pathways for movement” (152). These studies
underscore the need for advanced psychophysical testing
various cerebral structures in fatigue.
and therapy for such patients and suggest that the sense
CelLuLar issues.It may be possible to explore the celluof effort may entail at least two componen ts: one assolar basis of the sense of effort. A substantial database
ciated with the impairment
of performance an .d another
exists on the impulse traffic between suprasegmental
and segmental centers during the elaboration of moveof “higher” pathophysi .ological origin, wherein t he perment, , as recorded in conscious prim ates trained to per- ceived effort does not relate directly to motor perforform av ariety of motor tasks. The data consist of the mance.
activity of single cells recorded from a number of supraSummary. Although changes in the perceived effort
composegmental structures and then related to the kinematic
a.ssociated w ith a task represent an important
and kinetic details of the movement. This approach , pio- nent of fatigue, little is known about the behavioral and
basis of this sensation. However, the
neered by Evarts in the 1960s has provided a mea ns to neurobiological
determine the relative roles of the cerebral cortex, basal psychophysical
and neurophysiological
techniques to
ganglia, and cerebellum in the control of movement. This
study the sense of effort are currently available, and
work includes the demonstration
of corticopetal input
there is a demonstrated clinical need for systematic studfrom primary sensory afferents during movement, but ies in this area. Studies are needed to I) quantify the
not of corollary discharges from lower spinal centers, as relationship between the sense of effort and the decline
has been achieved in primate visual centers and the spi- in force for different muscle groups and tasks, 2) examnal centers of other species [electric fish, cat (7, 154)]. It ine the effects of fatigue on tasks for which sensory feed3 ) assess the effects of
now seems appropriate to extend Evarts’ technique to back is kn .own to be important,
fatigue on timing judgments and the means by which
POPUlation analyses (104a) in the study of suprasegmencorollary discharge may mediate this percep tion,h) chartal aspects of muscle fatigue to address the following
acterize the relationship between the sense of effort and
questions. 1) Can a neu ronal basis for coral .lary discharge
at various levels of the neuraxis be established in the the . readiness potential, 5) use established electrophysioconscious primate? 2) What is the temporal relationship
tee hniques to explore the cellog1 .cal population-analysis
between changes in corollary discharge and force failure
lular basis of the sense of effort, and 6) exten .d psychoduring fatigue? 3) Does fatigue influence the association
physical procedures to study the sense of effort in clinical
populations.
between corticopetal input driv en by corollary discharge
and the timing o f muscl e contracti ons? 4) Is corollary
Conclusions
discharge during fatigue influenced by peripheral afferent feedback? Studies that address such issues shou Id
Fatigue is a concept that encompasses a class of acute
con tribute to our unde rstanding of the cellular basis of effects that impair motor performance. We have identith .e sense of effort.
fied four themes that provide a basis for the systematic
study of fatigue.
Clinical issues.Al thou gh muscle fatigue is a prominent
symptom in a wide variety of diseases of the CNS and the
I) Task dependency. The specific mechanisms
that
peripheral neuromuscular
system, there are no recent
cause fatigue in a given condition are determined by the
details of the task performed by the individual;
these
systematic accounts of its prevalence in the clinical literature. This situation is changing at the peripheral neuromechanisms can include the CNS drive to motor neumuscular level of clinical inquiry, where electrop hysiolrons, the muscles and motor units that are activated,
neuromuscular propagation, excitation-contraction
couogy, muscle biopsy biochemistry,
and nuclear magnetic
BRIEF
pling, the availability of metabolic substrates, the intracellular milieu, the contractile apparatus, and muscle
blood flow. Task variables that can influence the prevailing mechanism include the level of motivation of the subject, the intensity and duration of the activity, and the
extent to which the activity is continuously
sustained
(isometric vs. dynamic). Studies are needed that identify
the boundary conditions and interactions between these
mechanisms during human performance.
2) Force-fatigability
relationship. For most, but not all,
experimental conditions, the greater the force exerted by
a muscle or motor unit for a given task, the more the
muscle will fatigue. This suggests that the mechanisms
underlying fatigue scale with the force that is exerted.
There is a need to systematically explore the force-fatigability domain for a variety of muscles and tasks to determine the global nature of the relationship and to identify local regions where the relationship
is nonmonotonic.
3) Muscle wisdom. One set of adaptations
that has
been associated with sustained activity includes a concurrent decline in force, relaxation rate, and motor neuron
discharge. This association has been termed “muscle
wisdom,” because it optimizes the force and ensures an
economical activation of fatiguing muscle by the CNS.
The mechanisms underlying muscle wisdom remain to be
identified.
4) Sense of effort. The perceived effort associated with
a task, which represents an important component of fatigue, is derived from centrally generated motor commands (and perhaps their formulation)
that give rise to
corollary discharges. Little is known about the interaction between changes in the sense of effort and force
failure in fatigue, although the techniques to study the
sense of effort are available and a clinical need for information on this topic has been demonstrated.
The authors are grateful
to Drs. Enzo Cafarelli,
Andrew
Fuglevand,
Simon Gandevia,
Lynette
Jones, and David McKenzie
for comments
on a draft of the manuscript.
This work was supported,
in part, by National
Institutes
of Health
Grants
AG-09000,
GM-08400,
NS-25077,
HL-07249,
NS-07309,
and
RR-05675
and National
Science Foundation
Grant INT-852083.
Address
for reprint
requests:
R. M. Enoka,
Dept. of Exercise
and
Sport
Sciences,
Gittings
Bldg., University
of Arizona,
Tucson,
AZ
85721.
REVIEW
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
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