How important is endogenous muscle glycogen to fatigue in prolonged exercise?

Endogenous muscle glycogen represents a primary fuel source during large muscle group activity in the human. The depletion of this fuel source during submaximal exercise at intensities ranging between 60 and 85% of maximal aerobic power (Vo2max) is widely believed to be the cause of an inability to sustain exercise. Alterations of preexercise muscle glycogen reserves by dietary and exercise manipulations and changing the degree of dependency on endogenous glycogen during exercise by modifying the availability of other fuel sources have in general served to establish a close relationship between muscle glycogen and fatigue resistance. However, in spite of the evidence implicating glycogen depletion to fatigue, the mechanism remains elusive. The most popular theory is that glycogen is an essential substrate, the depletion of which results in a reduction in the rate of ATP regeneration and an inability to maintain energy supply to one or more of the processes involved in excitation and contraction in the muscle. As a consequence, the muscle is unable to translate the motor drive into an expected force and fatigue develops. However, there is little experimental evidence to support this theory. Most studies report no or only minimal changes in ATP concentration at fatigue with low glycogen and no further change in the by-products of ATP hydrolysis. These findings suggest that fatigue might be caused by other nonmetabolic factors. This review examines these other nonmetabolic factors and analyzes their potential role in fatigue during prolonged exercise with depletion of muscle glycogen reserves.