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

E. R. Chin, C. D. Balnave and D. G. Allen Institute for Biomedical Research and Department of Physiology, University of Sydney, New South Wales, Australia. 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 microM x s, respectively. Only the intermediate and long series resulted in prolonged (>60 x 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: 1) 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.