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Section 2 the Mechanic of Muscle Fatigue
2 Reduced
Excitation of the
Motoneurnons
（1）Reduced
Supraspinal
Drive to the
Motoneurons
（2）Changes in
the Input to the
Motoneurons
From the
Periphery
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2 Reduced Excitation of the Motoneurnons
 Several factors contribute to reduced excitation of spinal motorneurous.
Basically ,any reduction in the excitatory drive and/or increase in inhibitory
influence acting on the motoneurons, whether from subpraspinal levels, from
the segmental circuitry, or from the periphery, will reduce firing rates.
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（1）Reduced Supraspinal Drive to the
Motoneurons
 Not only acute reduction in activity but also long-term reductions, such as
during limb immobilization, have been reported to disproportionately reduce
maximal voluntary force compared with twitch and tetanic forces. This may be
taken to indicate that voluntary muscle activity is necessary to retain the
ability to produce high levels of drive to the motoneuron pool . In a way ,the
reduced drive following a period of inactivity can be regarded as the inverse of
neural adaptation to strength training . A similar explanation may be offered
for the greater prevalence of central fatigue in older subjects reported by
Bilodeau et al.(2001).
 Change in the human motor cortex have been shown to accompany central
fatigue. Experiments with transcranial magnetic stimulation（TMS）in
healthy humans have shown decreased intracortical facilitation after fatiguing
exercise, and the changes were contined to the areas of the motor cortex
involved in the fatiguing contractions. The mechanisms behind these changes
could not be established, although events upstream of the motor cortex have
been considered to be possible candidates（Tergau et al.2000）, such as
supraspinal effects of group Ⅲand Ⅳ muscle afferents (Gandevia 1998). As
alluded to previously, this means that elements of central fatigue could
originate in the periphery.
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
Although little is known about the neurophysiological or biochemical
mechanisms behind central fatigue ,some theories exist, one of which is the
so-called branched-chain amino acid (BCAA) theory. The main points of this
theory are as follows:
1、BCAAS and tryptophan enter the brain via the same amino carrier, and
competition between the two types of amino acid for entry into the brain can
occur.
2、In the brain ,tryptophan is converted to the neurotransmitter 5hydroxytryptamin（5-HT）, also known as serotonin, which is known to
promote sleep and tiredness, a fact that makes it a possible fatiguepromoting substance.
3、During physical activity ,BCAAs are taken up by muscle, shifting the balance
between the plasma concentrations of tryptophan and BCAAs in the
direction of trytophan. This can increase the uptake of tryptophan in the
brain and the subsequent formation of 5-HT(Newsholme and Blomstrand
1995).
So far ,however ,this remains a theory because experiments involving
ingestion of tryptophan and BCAAs during sustained exercise have failed to
show a performance effect (Van Hall et al.1995).
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（2）Changes in the Input to the
Motoneurons From the Periphery
 In conscious humans ,fatiguing muscle contractions are accompanied by a
decreased in the firing rates of a motoneurons. This has been interpreted as a
mechanism to ensure proper matching between motoneuron firing rate and
muscle unit force output and is commonly referred to as muscle wisdom
 During a fatiguing maximal voluntary contraction ,the electromyographic
activity declines roughly in parallel with the loss of force. This decline has
been attributed to reflex inhibition of the motoneuron pool .
 Oligosynaptic spinal pathways are likely contributors , possibly mediated by
group Ⅲ(corresponding to group A) orⅣ(corresponding to group C) muscle
afferents, which are known to be activated by muscle contractions . Group Ⅳ
contains unmyelihated nerve fibers responsive to pain stimuli, whereas group
Ⅲ are thin, myelinated fibers responsive to pain and temperature stimuli.
Neuropharmacological research has shown that some group Ⅲ and Ⅳ muscle
afferents—the so called capsaicin-sensitive nerves－are responsive to protons
as well. There is a good correlation between tissue PH and afferent discharge
when the PH falls to 6.6 or less , and the resulting inhibition of motoneurons
can be regarded as a protective mechanism.
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（2）Changes in the Input to the
Motoneurons From the Periphery
 however , there was not a parallel decline in motorneuronal firing rate ,
the activation of motor units would become supratetanic, and rate
coding as a means of force modulation would be ineffective . this is the
reason why the phenomenon has been named muscle wisdom.
 Muscle spindles are the main source of afferent excitation from the
periphery , and spindle afferent activity declines during muscle
contraction . Blockade of spindle afferents reduces motoneuron firing
rates , indicating that fusimotor-mediated spindle facilitation is
necessary to reach peak rates . Although spindle afferent activity
declines during static contractions, resulting in a disfacilitation of a
motoneurons (figure 15.6), the situation could be different during
dynamic contractions. During concentric work , fusimotor drive is
insufficient to compensate for muscle shortening, and spindle afferent
become silent. In eccentric contractions ,on the other hand , the stretch
sensitivity of muscle spindles increase, which increase the ability in
spindle afferents and increase muscle stiffness .
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3 Factors Affecting
Generation of an
Endplate Potential
（1）Motor
Axon
propagation
Failure- Branch
Failure
（2）Fatigue at
the
Neuromuscular
Junction
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（1）Motor Axon propagation Failure- Branch Failure
 It has been known for quite some time that action potentials can fail to
propagate along each branch of a motor axon , and that failure is likely to
occur at axonal branching points. Experiments have suggested that shifts in
the ionic balance over the axon membrane could be responsible (figure 15.7).
such ionic perturbations are more likely to occur in smaller axons , because the
surface-to-volume ration is larger in thin axons than in thicker ones, and they
are more likely to occur during high-frequency stimulation.
Consequently ,branch failure is believed to start peripherally and spread
gradually in a centripetal direction.
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（1）Motor Axon propagation Failure- Branch Failure
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（1）Motor Axon propagation Failure- Branch Failure

The most peripheral branch points are the terminal branchings of the
axon as it approaches each
 Muscle fiber (cf. figure 3.9). For each individual axonal branch ,the
effect of the ionic perturbations on action potential propagation is
probably transient, meaning that an affected synaptic terminal within
the motor endplate is not completely silenced, but that occasional
action potentials are missing, decreasing the firing rate for that
particular terminal at the level of muscle fiber and reducing the safety
factor of the motor endplate in question.
 A branch failure where the axon divides into separate branches for
each muscle fiber will inevitably reduce impulse frequency to the
muscle fibers innervated by the affected branches and will
correspondingly reduce the force contribution of those muscle fibers
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（2）Fatigue at the Neuromuscular
Junction
 The successful transmission of an action potential in a motor endplate depends
on the size of the combined EPSPs (excitatory postsynaptic potentials, see
chapter 4) of all the synaptic terminals of the synaptic terminals of the
endplate in relation to the threshold for muscle fiber action potential
generation.
 Theoretically , a transmission failure at the neuro-muscle junction may be the
result of each of the following factors or a combination of them: a reduced
number of discharging synaptic terminals , a reduced number of synaptic
vesicles in the discharging terminals, a reduced sensitivity of the Ach receptors
(AChRs) in the postsynaptic membrane (figure 15.8).
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（2）Fatigue at the Neuromuscular
Junction
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（2）Fatigue at the Neuromuscular
Junction
 A reduced number of discharging synaptic terminals in a motor endplate can
result from a branch failure within the terminal arborization of the axon , as
outlined previously. To a certain extent, this can be handled by the safety
factory. The safety factor for type Ⅱ muscle fibers has been reported to be
larger than for type Ⅰ fibers, but for both fiber types it is large enough to
ensure reliable neuromuscular transmission under nonfatigued conditions. On
repetitive stimulation, however, the safety factor for type fibers remains
unchanged, whereas that of type Ⅱ fibers rapidly declines . The reason for this
difference is so far speculative. It is also unknown how and to what extent the
ionic perturbations created by repeated muscle fiber action potentials
influence propagation in the neighboring terminal branches of the axon.
 During postnatal growth , both muscle fibers and motor endplates increase in
size , the latter relatively more than the former, thus increasing the size of
motor endplates in relation to muscle fiber size. In accordance with
this ,newborn rats have been found to be more susceptible to neuromuscular
transmission failure than adult animals. In line with this , the relative
increasing in the size of endplates seen in animals subjected to training can be
taken as an indication that training confers resistance to neuromuscular
transmission failure. For natural reasons , corresponding findings in humans
are lacking .
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Summary
 Muscle fatigue can be categorized as central or peripheral, but it should be
acknowledged that the words central and peripheral are not used in the
anatomically correct way. The main reason for this are that the definition of
central fatigue is operational, and that factors leading to central fatigue may
have their origin in the periphery. Central fatigue is said to be present when
maximum voluntary force is less than maximal evocable force. The
interpolated twitch technique is the main method to separate central from
peripheral fatigue.
 Transcranial magnetic stimulation has revealed the presence of decreased
intracortical facilitation after fatiguing exercise, and the changes are confined
to the somatotopically relevant parts of the motor cortex. The changes,
however ,could be secondary to changes in afferent activity to the motor cortex.
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Summary

For normal ,rested muscle , the launching of an action potential from
the motoneuron is the point of no return in muscle control. Thus, in
nonfatigued muscle, any change in the balance between excitatory and
inhibitory inputs to the motoneurons , in favor of latter, will reduce the
impulse frequency to the muscle units and tend to lower their force
input. This can be attributed to reduced supraspinal drive or reduced
muscle spindal afferent actibity. Theoretically ,failure of propagation
of the nerve action potential (brance failure) and neuromuscular
transmission failure also can be give rise to central fatigue, but the
practical importance of this is probably limited, at least in daily life.
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4 Fatigue Attributable to Processes Beyond the
Neuromuscular Junction-Peripheral Fatigue
（1）Failure in the propagation
of the muscle fiber
action potential-high-frequency fatigue
（2）Fatigue at the T-Tubule- Sarcoplasmic
Reticulum Junction-Low-Frequency Fatigue
（3）Myofibrillar Fatigue
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（1）Failure in the propagation of the muscle fiber
action potential-high-frequency fatigue
 Indirect evidence indicates that failure in the propagation of muscle action
potentials along the T-tubules plays an important role, and this has been
attributed to accumulation of K+ in the T-tubule lumen. Theoretically, the Ttubules would be expected to be the more susceptible to ionic perturbations
because of repetitive stimulation. First , the lumen is very small in relation to
the T-tubule membrane. Second ,the density of Na+-K+ ATPase molecules(the
sodium-potassium pump) has been claimed to be lower in the T-tubule
membrane than in the surface membrane, and the more important effects of
an increased extracellular K+ concentration have been considered likely to
involve excitation-contraction coupling via the T-tubules , rather than the
excitability of the surface membrane. However , human studies provided
support for the possible role of T-tubules in high-frequency fatigue(HFF),
because a kind of fatigue resenmbling HFF result from stimulation of human
tibialis anterior muscle under ischemic conditions. Muscles held at shorted
length during stimulation fatigued more than muscles held at optimum length.
Both groups recovered substantially after cessation of stimulation, although
still ischemic, but the muscle fatigue in the shortened position showed further
recovery when returned to optimum length. These results are consistent with
restricted movement and consequent accumulation of K+ in the lumen of Ttubules, possibly because of narrowing of their openings to the surface of the
fibers when in the shortened position.
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（1）Failure in the propagation of the muscle fiber
action potential-high-frequency fatigue

Indirect support for a propagation failure in the T-tubules comes
from the demonstration in freeze-clamped fatigued muscle fibers that
centrally located myofibrils had a wavy appearance, indicating that
they were less activated and thus longer than more peripherally
located myofibrils.
 HFF is induced by high-frequency stimulation, and it has been
questioned whether HFF is a physiologically relevant and “normal”
type of fatigue, mainly because the frequencies necessary to induce
HFF are higher than those thought to occur during normal sustained
isometric contractions. On the theoretical basis, it has been calculated
that Na+-K+ ATPase is able to keep pace with the influx of sodium ions
and efflux of potassium at excitation frequencies up to around 55Hz .
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（2）Fatigue at the T-Tubule- Sarcoplasmic
Reticulum Junction-Low-Frequency Fatigue

In 1997, Richard Edwards and coworkers described a type of muscle fatigue
that they called low-frequency fatigue (LFF).it was characterized by being
most pronounced at low frequencies (figure 15.9) and by having a very slow
recovery –in fact taking hours, maybe days ,despite absence of any signs of
metabolic or electrical disturbance in the muscle. the slow recovery is in sharp
contrast to the very fast recovery is in the sharp contrast to the very fast
recovery , in the order of minutes, seen after HFF.
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（2）Fatigue at the T-Tubule- Sarcoplasmic
Reticulum Junction-Low-Frequency Fatigue
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（2）Fatigue at the T-Tubule- Sarcoplasmic
Reticulum Junction-Low-Frequency Fatigue
 The slow recovery indicated that some kind of repair process involving
protein synthesis was necessary , and this suspicion was strengthened
by the fact that LFF is common after eccentric contractions , a type pf
muscular activity known to cause substantial damage.
 LFF was accompanied by a uniform reduction of cytosolic calcium
across the fatigue muscle fiber, whereas no change was seen in calcium
sensitivity or in maximal calcium-activated tension, thus settling the
previously mentioned uncertainty. It remained unknown, however,
what was responsible for the reduced calcium levels. Furthermore,
although decreased cytosolic calcium has been shown during LFF, it
may not be the only cause ; a redistribution of sarcomere lengths also
has been suspected to contribute to LFF. Binder-Macleod and Russ
presented evidence in support of two factors contributing to LFF：one
rapidly recovering , metabolite-dependent mechanism, and a slowdeveloping, slow-recovering factor, which is not the result of any
metabolite buildup.
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（3）Myofibrillar Fatigue
 Fatigue caused y inability of the muscle fiber to react properly to elevated
cytosolic Ca2+ concentration is called myofibrillar fatigue. In such cases , the
force/Ca2+ concentration curve is shifted to the right ,but this has been shown
only for type Ⅰfiber. Under these circumstances , caffeine-induced elevation of
cytosolic Ca+2 concentration is unable to increase force (figure 15.11).
 In normal , rested muscle , the force per sarcomere is proportional to the
number of active across-bridges. Theoretically ,a reduced force output despite
unchanged sarcomere length and cytosolic Ca2+ concentration can be
attributable to a reduced number of active cross-bridges or a reduced force per
cross-bridge.
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（3）Myofibrillar Fatigue
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（3）Myofibrillar Fatigue
 Fatigability of Different Fiber Types：There are typical different in the
fatigability of human muscle fiber types. TypeⅠfibers are the more fatigue
resistant, type ⅡX the least, and type ⅡA intermediate. This is demonstrated
very clearly by figure 15.12, which shows the correlation between percentage
of type ⅡX fibers in human quadriceps muscle and peak torque decline after
50 maximal knee extensions . The open circles in figure 15.12 denote
individuals with less than 35% type Ⅱ fibers, that is, with more than 65%
typeⅠ. Part of the variation also could be attributable to the fact that
differences between “identical” fiber types in different individuals are even
larger than difference between different fiber types within one muscle. this is
caused by differences in individuals’ training status and can even apply to
difference between muscles in different parts of the body in one individual,
depending on his or her training level.
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（3）Myofibrillar Fatigue
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（3）Myofibrillar Fatigue
 Basically, the different fatigue resistance of muscle fiber types derives from
three characteristics: contractile economy, oxidative capacity, and relative
training status, which among other things is subsequent to their rank in the
recruitment hierarchy.
 The relative oxidative potential of the different muscle fiber types is
typeⅠ>typeⅡ>typeⅡX, which also contributes to the differences in fatigue
resistance between the muscle fiber types. Because the oxidative potential of a
muscle fiber is highly trainable, the fatigue resistance of low- threshold
typeⅠmuscle fibers may be attributable in part to their recruitment history.
The size principle governs the recruitment of motor units during isometrix and
concentric work. In these cases, the recruitment hierarchy can be likened to a
flight of stairs, which has to be climbed from the bottom every time, regardless
of how high you have to climb.
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Summary
 Peripheral fatigue is the kind of fatigue that is not alleviated by direct
stimulation of the muscle by the twitch interpolation technique. It can be
caused by factors affecting the propagation of muscle action potentials along
the surface membrane and into the T-tubules, factors affecting the release of
calcium from the sarcoplasmic reticulum, or factors affecting the response of
individual myofibrils to increase levels of cytosolic calcium.
 Propagation failure is mostly seen after unphysiologically high stimulation
frequencies and seems to be of limited importance in daily life. Such HFF is
rapidly reversed when the fatiguing activity is terminated, and it is believed to
be caused by ionic perturbations, in particular a loss of K+ from the cytosol to
the extracellular space. Ionic perturbations in the T-tubule are often claimed to
be responsible for failure of T-tubule are often claimed to be responsible for
failure of T-tubule function, but direct evidence is lacking.
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Summary
 Failure in the calcium release process gives rise to a characteristic force deficit,
which is more pronounced at low than at high stimulation frequencies, hence
the name LFF. In contrast to HFF,LFF shows a very slow recovery, indicating
that molecules critically involved in the calcium release process are seriously
damaged and in need of replacement . the mechanism behind this process is
not known yet, but elevated levels of calcium are implicated, phenomenon
referred to as the calcium paradox.
 Inability of the individual myofibrils to respond properly to increased levels
of cytosolic calcium is called myofibrillar fatigue. It can be caused by a
decreased number of active across-bridges or a decreased force per active
across-bridge.
 TypeⅠis the most fatigue-resistant muscle fiber type, typeⅡX is most easily
fatigue. This differences is based on three characteristics: muscle fiber
contractile economy, oxidative capacity, and relative training status,
subsequent to their rank in the recruitment hierarchy.
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