MUSCLE FATIGUE
Talk by Dr Graham Lamb (La Trobe University) 19/9/01
(Check “Downloads” for papers related to this talk.)
What is muscle fatigue? It is a decline in force production.
It is the muscle itself, not CNS or NM junction, which is responsible for fatigue.
There are various causes of muscle fatigue, depending on the muscle type
and the strength and duration of the stimulation. Action potentials (APs)
trigger muscle contraction by a sequence of steps referred to as ‘Excitationcontraction coupling’. Reduced force production can occur because of failure
in one or more of these steps, in particular a) failure of APs to propagate, b)
failure to raise intracellular [Ca2+] sufficiently, or c) reduced responsiveness of
the contractile apparatus.
Muscle structure:
Skeletal muscle, and to a lesser extent cardiac muscle, has a regular network
of invaginations in the surface membrane called the ‘transverse tubular (T-)
system’. These tubules are very narrow, but so extensive that there is about
five times more surface area down the tubules than on the surface of the
muscle fibre. The T-system is filled with extracellular fluid and allows APs to
propagate all through the muscle fibre, ensuring synchronous activation. The
T-system butts up against the sarcoplasmic reticulum (SR), the intracellular
Ca2+ store, though the two membrane systems are physically separate. APs
in the T-system trigger Ca2+ release from the SR by very different
mechanisms in cardiac and vertebrate skeletal muscle.
Excitation-contraction coupling:
In both skeletal and cardiac muscle, a rise in intracellular [Ca2+] from about
0.1 M to >1 M activates the contractile apparatus leading to contraction. In
neonatal tissue, much or all of this Ca2+ comes from the influx of extracellular
Ca2+ (~2 mM). However, in the larger cells of adult tissue most of the Ca 2+
comes from internal stores (the sarcoplasmic reticulum, SR) not from the
extracellular solution – this may be a way to overcome diffusional delays over
larger distances. The problem then is how to release the Ca2+ from the stores
when required.
In cardiac and invertebrate skeletal muscle this is done by using the influx of
extracellular Ca2+ as a trigger to release Ca2+ from the internal stores, the socalled “Ca2+-induced Ca2+ release” mechanism. The full sequence is as
follows: An action potential travelling over the surface of the muscle cell opens
voltage-dependent Ca2+ channels (dihydropyridine receptor proteins (DHPs))
in the surface membrane, allowing the entry of extracellular Ca2+ into the
sarcoplasm. This Ca2+ binds to high affinity sites on the Ca2+ release channel
proteins (also known as ryanodine receptors) in the SR, causing the channels
to open and let out Ca2+ from the SR. (The DHP family of drugs can be used
reduce the force of heart contraction as a treatment of some types of heart
disease – this works because the DHPs partially block the surface Ca 2+
channels (the DHP receptor proteins), thereby reducing Ca2+ influx which in
turn reduces Ca2+-induced Ca2+ release from the SR).
In vertebrate skeletal muscle, there have been a number of evolutionary
changes, probably to enhance the speed and control of Ca 2+ release and
hence contraction. Firstly, the influx of extracellular Ca 2+ is not necessary for
triggering Ca2+ release from the SR. The DHP receptor/voltage-dependent
Ca2+ channels in the T-system (also known as ‘voltage-sensors’, (VS))
physically couple by a protein-protein interaction with the Ca2+ release
channels in the SR. Secondly, the sensitivity of the Ca2+ release channels to
cytoplasmic Ca2+ is much lower than in cardiac muscle – this is due to a
strongly enhanced inhibitory effect of intracellular Mg2+ on the release
channels. The overall effect of these two changes is that the DHP
receptor/voltage-sensor controls the Ca2+ release channel directly, not by a
‘Ca2+-induced Ca2+ release’ mechanism, with the consequence that Ca 2+
release can not only be activated in milliseconds, but can also be stopped in
milliseconds, a necessary requirement for rapid, accurate muscle control.
Muscle fibre types:
In mammals: slow twitch is Type I and fast twitch is Type II.
Slow twitch: - red appearance
- many mitochondria, lower force output
- fatigue “resistant”, postural or repetitive role.
Fast twitch: - white appearance, fewer mitochondria, high force output, faster
contractions and relaxation, fatigue faster.
- recruit for “explosive” contraction.
Types of muscle fatigue
 High frequency fatigue – onset in seconds. Fast and full
recovery in seconds.
 “Metabolic” fatigue.
 Long duration fatigue (takes a long time to recover).
K+
Na+
Ca2+
VS
Transverse tubule in muscle
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Ca2+ Release
Channel
Ca2+ store in
Sarcoplasmic
reticulum
High Frequency Fatigue:
Each AP leads to Na+/K+ movement. A large number of APs will produce an
increase in [K+] in the tubules leading chronic depolarization of the T-system
(eg. from –90 mV to ~-60 mV), which prevents the voltage-dependent sodium
channels in the T-system from resetting (ie. they stay ‘inactivated’). In the
extreme, this would mean APs would not propagate into and along the Tsystem, and hence there would be no activation of the voltage-sensor (VS)
coupling to the Ca2+ release channel, and hence no muscle contraction. This
is called high frequency fatigue. It is induced rapidly (ie. over seconds) by
high frequency stimulation (eg. 100 – 200Hz), but recovery is also very rapid
(over seconds) upon cessation of stimulation due to K + both diffusing out of
the T-system and being pumped back into the cell by the Na-K-ATPase in the
T-system membrane. This type of fatigue is not caused by metabolic changes
within the fibre.
Metabolic Fatigue:
When a muscle has been stimulated sufficiently long and/or vigorously there
can be metabolic changes within the fibre. This will occur differently in fast
and slow-twitch fibres. The metabolic changes could cause reduced Ca2+
release from the SR and/or reduced responsiveness of the contractile
apparatus.
Energy production reaction:
ATP

ADP + Pi
Muscles have stores of high-energy phosphates: 8 mM ATP and 50 mM
creatine phosphate (CrP). Normally [ATP] is kept close to 8 mM by the
resynthesising it from ADP using the CrP.
Resynthesis of ATP from ADP
CrP + ADP

ATP + Cr
This is a fast reaction – keeps [ATP] high and [ADP] low.
The net reaction: CrP
 Cr + Pi
ATP is used at ~1 to 2 mM/s during maximal contraction (by the contractile
apparatus and the SR Ca2+ pump). This means that all the CrP will be
exhausted within ~30 to 60s. If this happens [ATP] will fall, and also [Mg 2+]
will rise (most cellular Mg2+ is normally bound to ATP), and if unchecked,
ultimately the cell would die due to ATP exhaustion and consequent failure to
keep cytoplasmic [Ca2+] relatively low. This is why having a ‘fatigue’
mechanism is essential – there is a clear advantage to having a system which
will shut itself down before it exhausts the cellular ATP supply.
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Muscles can function for long periods of activity so long as the energy use is
matched to supply. In slow-twitch muscle in general ATP usage is met by
aerobic respiration.
Aerobic respiration: 36 ATP produced per glucose molecule.
ATP can also be produced by:
a) Anaerobic respiration: Glucose +2 ADP + 2 Pi  2 ATP + 2 lactic acid
b) 2ADP  ATP + AMP
(AMP is deaminated to IMP and there is reduction in available ATP).
This is a very inefficient process. The muscle here is being pushed very hard.
Metabolic changes occurring during exercise
Fast-twitch muscle undergoing intense exercise (anaerobic)
Early term: Cr  , Pi  , lactate  , H+  progressively.
Medium term: ATP  , Mg2+  , IMP 
Slow-twitch – low to medium intensity exercise (aerobic)
Early to medium term: Cr  , Pi  progressively, some lactate  , H+ 
Longer term: glycogen 
Which of the above cause muscle fatigue?
Direct effects on the contractile apparatus: The rise in P i will directly reduce
the Ca2+ sensitivity of the contractile apparatus to some degree though this is
largely offset by the effect of the concomitant reduction in CrP. Overall there
is only a small reduction in the maximum force production and Ca 2+ sensitivity
of the contractile apparatus – the most dramatic effects are due to reductions
in Ca2+ release.
Experiments in which lactate is added to isolated muscle fibres has shown
that lactate has no effect on Ca2+ release and contractions. The same is also
true for raising intracellular [H+] (this has been shown recently to actually
reduce high frequency fatigue).
Instead, the three primary causes of reduced Ca 2+ release areas follow, the
first two probably being most important in slow-twitch fibres and the third in
fast-twitch fibres:
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
Increase in [Pi]. Some Pi moves into the Ca2+ store (sarcoplasmic
reticulum). This Pi precipitates Ca2+ which then reduces the free Ca2+
available for release from the SR.

Glycogen depletion. This is deleterious both because of the limitation
of aerobic metabolism and also because of a poorly understood effect
in which glycogen depletion directly inhibits the coupling between the
VS and the Ca2+ release channels, possibly because of the liberation of
associated enzymes.

Decrease in [ATP] (and the accompanying increase in [Mg2+] and
metabolites of ATP). The Ca2+ release channel has a low affinity
binding site for ATP (dissociation constant ~ 1 mM), and only when
ATP is on this site can the channel be activated. Thus, if [ATP] drops
to <1 mM it is difficult to fully activate the Ca2+ release channel. Any
build-up of ADP and AMP will worsen this because they compete for
the same site but don’t cause much stimulation. The concomitant
increase in free [Mg2+] also inhibits the Ca2+ release channel directly.
Long–duration fatigue (also known as ‘low-frequency fatigue’) is caused by
Ca2+ induced damage where Ca2+ moves in and out of the SR for too long.
This can also lead to structural changes or damage resulting in very
prolonged fatigue.
Muscle-fatigue – is it all bad?
No – it is a vital fail-safe mechanism. If [ATP] decreases and almost runs out
then cellular death could occur. Then fatigue is a self-limiting mechanism.
That also suggests that there must be sensors for [ATP].
Should creatine be taken as a supplement? Some studies claim creatine
supplements can reduce muscle fatigue and others say it has no effect or can
be deleterious. Some reports have associated it with undesired weight gain.
One would expect it to be of most use for preventing the type of fatigue
occurring in fast-twitch fibres with vigorous stimulation. However, it is not
clear that ingesting creatine raises muscle creatine levels, nor that this will
raise the creatine phosphate levels – raising creatine alone would worsen the
energy balance.
Muscle meltdown.
This happens due to exhaustion and when muscle temperature increases to
about 41o. Contractile apparatus becomes dysfunctional, all of the ATP is
used up and proteases are activated. Heat-shock proteins are also activated.
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