Fatigue in Skeletal Muscle
Fatigue During High-Intensity Exercise | Fatigue During Prolonged Exercise
Fatigue During High-Intensity Exercise
An individual’s capacity to perform during
high-intensity exercise depends upon his/her ability to generate and maintain a
high power output. That ability requires both a high anaerobic capacity and the
functional ability to generate the necessary force and velocity for a given
power requirement. Peak force and power output of a muscle depend upon numerous
factors, but the most important are: muscle size, force per cross-sectional
are, the peak rate of force development, and the maximal speed of muscle
shortening (Vmax). The inability to maintain the desired power
output defines fatigue, and mechanisms that attempt to explain fatigue have
been generally classified as product accumulation or substrate depletion.
Calcium as A Limiting Factor
The peak rate of force development is thought
to be limited by the rate of myosin binding to actin. This rate has recently
been shown to be directly regulated by Ca2+. Moreover, a decline in
force output can be traced, in part, to a decreased release of Ca2+ from
the sarcoplasmic reticulum (SR). The action potential that travels along the
sarcolemma and down the transverse-tubules signal the SR to release Ca2+ into
the sarcoplasm. The Ca2+-release channels open to allow diffusion of
Ca2+ into the sarcoplasm, and reuptake is carried out by the Ca-pump
(i.e. the Ca2+-ATPase). FT fibers are known to contain more SR, and
hence more Ca2+ -ATPase, than ST fibers. Also, the speed of
contraction, and especially relaxation rate, seems closely associated with the
number of available Ca-pumps. Moreover, the Ca-pump is a major ATP consumer
during both rest and activity. The relative cost of the Ca-pump is
approximately 30% of the total ATP turnover during isometric contraction.
Recent experiments on isolated muscle cells
have linked reduced sarcoplasmic [Ca2+] to fatigue. Reduced peak Ca2+
release probably was not a consequence of impaired t-tubule conduction,
but rather the inability of either the signal to the SR or its inability to
release Ca2+. Furthermore, force output decreases with a lower
intracellular pH possibly due to a reduced sensitivity of the contractile
elements to Ca2+. Another aspect is that the prolonged relaxation
time observed with high-intensity exercise is closely related to a depression
of rate of Ca2+ uptake.
ATP as A Limiting Factor
Insufficient intramuscular [ATP] is often
thought to be the cause of fatigue, although considerable evidence suggests
this might not be the case. Numerous studies have demonstrated that [ATP] falls
no more than ~70% of preexercise levels during high-intensity exercise.
However, there is speculation that 70-80% of the sarcoplasmic ATP is restricted
to the mitochondria and unavailable to the cross-bridges. In other words, ATP is
"compartmentalized" and, while sufficient ATP is inside the cell, it
is not in the location where needed. A compelling argument against this
hypothesis, though, is that resting muscle would develop tension would from
rigor cross-bridges due to a lack of ATP. Yet, this does not occur.
CP as a Limiting Factor
CP is valuable as a buffer for energy
availability at the onset of exercise. CP levels rapidly decline within the
first few seconds to 5% - 10% of the preexercise value within 30 s. However,
the rate of CP depletion generally occurs more rapidly than force, and mixed
opinions remain as to whether CP depletion limits force production. As the
function of CP is to resynthesize ATP, and as [ATP] does not fall below 70% of
the preexercise level, this possibility may be unlikely unless one accepts the
hypothesis of ATP compartmentalization.
Nonetheless, several recent studies have
demonstrated high-dose creatine supplementation to enhance work output during
repeated bout exercise. While creatine supplementation did not increased peak
power output, the decline in work output from fatigue over the course of
repeated work bouts was diminished. Creatine supplementation at sufficient
dosages will increase the total muscular creatine pool in most individuals
within 2 days. However, the improved work output likely is the result of more
rapid CP resynthesis during recovery.
Hydrogen Ions As A Limiting Factor
Anaerobic glycolysis produces lactic acid
and, at a physiological pH, most of the lactic acid dissociates into H+
and lactate. While the majority of H+ produced in muscle is from
glycolytic products, there are also other contributors to intracellular H+
accumulation including a reduction of intracellular [K+], synthesis
of CP, and the buffering of CO2 produced in the mitochondria. The
decrease in muscular pH affects several sites in muscle which lead to fatigue.
Inhibition of glycolysis by H+. Increased acidity is associated with a decreased
transformation of phosphorylase b to the active a form, and
inhibition of phosphofructokinase (PFK). However, whether H+ inhibition
of glycolysis has a primary role in the generation of muscle fatigue is
questionable because [ATP] in muscle during exercise may not decline to levels
at which the myosin ATPase reaction would be slowed.
Inhibition of excitation-contraction
coupling by H+. A
decreased pH has been demonstrated to reduce the affinity of troponin for Ca2+.
This appears to affect Type II fibers more than Type I. While the mechanism is
not clear, H+ may compete with Ca2+ for the
troponin-binding site.
Effects of H+ on cross-bridge
cycling. Increased H+
accumulation also decreases Vmax and maximal tension development of
the fiber. Further, this affects Type II fibers more than Type I in part due to
different myosin isoforms. Myosin ATPase activity is reduced as pH is lowered
which would slow ADP release, the overall rate-limiting step of cross-bridge
cycling.
Accumulation of Inorganic Phosphate
Cooke et al. (1988) concluded that an
increase in intramuscular [Pi] increased the number of cross-bridges in the
weakly bound state, thus reducing tension development. Pi is released from the
myosin head with the transition from the weak to strong state. A higher
intracellular [Pi] inhibits Pi release from myosin leaving actomyosin complexes
in the weak state for a longer period of time.
Summary
Cellular mechanisms of muscular fatigue are a
complex phenomenon that includes failure at more than one site along the chain
of excitation-contraction events. Force output is decreased as well as
shortening velocity which suggests alterations in the kinetic properties of the
cross-bridges. Edman (1992) suggested that while fatigue can be traced to fewer
attached cross-bridges, the major portion of the force decline is attributable
to reduced force output of the individual bridge. In summary, the following
changes in cross-bridge function are likely to occur during muscle fatigue: (a)
a slight decrease in the number of cross-bridge interactions, (b) a reduced
force output of the individual cross-bridge, and (c) reduced speed of cycling
of the bridges during cycling. Likely factors responsible for these effects
include: failure of the t-tubule—SR signaling, increased intramuscular [H+]
and [Pi], and possibly localized ATP depletion.
Fatigue
During Prolonged Exercise
While far more is understood about fatigue
during prolonged exercise, the answers remain incomplete. In order for
metabolism and muscle functioning to continue, the muscle requires
carbohydrate. This substrate is essential for maintaining Kreb’s cycle
intermediates that gradually become depleted which clarifies the phrase,
"fats are burned in the flame of carbohydrates."
Depletion of muscle glycogen is generally
accepted as the primary cause of fatigue, although this may take 2 h or more
while exercising at 70% of VO2max or higher. Exercise can continue
although at a reduced intensity provided the blood glucose concentration is
adequate. Fatigue also occurs if blood glucose is allowed to fall, presumably
because of central fatigue. Although this does not affect the rate of muscle
glycogen utilization, endurance can be prolonged by the ingestion of
carbohydrates during exercise provided the intake occurs prior to the onset of
fatigue.
Another interesting hypothesis is that
fatigue is also related to depletion of muscle triglyceride stores. This is not
well understood largely because of the difficulty in accurately measuring this
substrate. However, at least one report observed longer endurance times
following a high-fat diet that increased preexercise intramuscular triglyceride
stores.
While not of metabolic origin, increased core
temperature and dehydration contribute to fatigue because of their effects on the
cardiovascular system. This can be minimized by regular ingestion of cold fluid
during the exercise.
Central Fatigue
While motivation has always been recognized
as a fatigue factor, recent evidence has finally begun to provide insight into
the central fatigue component. Serotonin, a neurotransmitter in the brain, is
associated with the onset of sleepiness, lethargy, and mood. And, in the brains
of exercising rats, levels of serotonin have been observed to increase during
prolonged exercise. This appears to be caused by increasing plasma levels of
free tryptophan, a precursor to serotonin synthesis.
During prolonged exercise as liver glycogen
is depleted, working muscles release increasing amounts of amino acids. Some of
amino acids are transported to the liver, converted into glucose, and released
in the blood in order to maintain blood glucose concentrations. Tryptophan, one
amino acid released from working muscle, is transported in blood primarily
bound to the protein, albumin. However, a small amount of tryptophan remains
unbound, and it is the free tryptophan which is thought to cross the blood-brain
barrier and synthesize serotonin. As exercise duration continues, more
tryptophan is released into blood, and Moreover, as more free fatty acids are
released from adipose tissue, which are also transported by albumin, the free
fatty acids tend to "bump" the bound tryptophan off of albumin. This,
and the increased release of tryptophan from muscle, further raises
concentrations of free tryptophan in blood resulting in greater serotonin
synthesis in the brain.
Carbohydrate feedings during exercise have been
shown to reduce fatigue and improve performance as well as decrease
concentrations of free tryptophan in blood. However, these studies have not
been able to separate whether the reduction of fatigue was due to a better
maintenance of blood glucose or decreased tryptophan release.
Suggested Reading
Davis, J.M. Carbohydrated, branched-chain amino acids and endurance: The central fatigue hypothesis. Gatorade Sports Science Exchange SSE#61, Volume 9 , Number 2, 1996. http://www.gssiweb.com