Role of intracellular calcium and metabolites in low-frequency fatigue of mouse skeletal muscle

We have examined the extent to which prolonged reductions in low-frequency force (i.e., low-frequency fatigue) result from increases in intracellular free Ca2+ concentration ([Ca2+](i)) and alterations in muscle metabolites. Force and [Ca2+](i) were measured in mammalian single muscle fibers in response to short,intermediate, and long series of tetani that elevated the [Ca2+](i)-time integral to 5, 17, and 29 mu M . s, respectively. Only the intermediate and long series resulted in prolonged (>60-min) reductions in Ca2+ release and low-frequency fatigue. When fibers recovered from the long series of tetani without glucose, Ca2+ release was reduced to a greater extent and force was reduced at high and low frequencies. These findings indicate that the decrease in sarcoplasmic reticulum Ca2+ release associated with fatigue has at least two components: I) a metabolic component, which, in the presence of glucose, recovers within 1 h, and 2) a component dependent on the elevation of the [Ca2+](i)-time integral, which recovers more slowly It is this Ca2+-dependent component that is primarily responsible for low-frequency fatigue.