Exertional
fatigue early in exercise is a clinical hallmark of muscle
glycogenoses, which is often coupled with painful muscle
contractures and episodes of
myoglobinuria. A fundamental biochemical problem in these conditions is the impaired generation of
ATP to fuel muscle contractions, which relates directly to the metabolic defect, but also to substrate-limited energy deficiency, as exemplified by the "second wind" phenomenon in
McArdle disease. A number of secondary events may also play a role in inducing premature
fatigue in
glycogenoses, including (1) absent or blunted muscle
acidosis, which may be important for maintaining muscle membrane excitability by decreasing
chloride permeability, (2) loss of the osmotic effect related to
lactate accumulation, which may account for absence of the normal increase in water content of exercised muscle, and thus promote higher than normal concentrations of extracellular
potassium in exercising muscle and (3) exaggerated accumulation of
ADP during exercise that may inhibit
sodium-
potassium and
calcium-
ATPases. Disorders of muscle glycogenolysis and glycolysis reveal the crucial role of these metabolic processes for supplying both anaerobic and aerobic energy for muscle contraction; and the pathological
fatigue that occurs when glycogenolysis and/or glycolysis is blocked imply an important role for theses metabolic pathways in normal muscle fatigue.