Fatigue in Skeletal Muscle
An individualís 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.
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-tubuleóSR signaling, increased intramuscular [H+] and [Pi], and possibly localized ATP depletion.
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 Krebís 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.
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.
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