Mechanisms underlying changes of tetanic [Ca2+](i) and force in skeletal muscle

Force development in skeletal muscle is driven by an increase in myoplasmic free [Ca2+] ([Ca2+](i)) due to Ca2+ release from the sarcoplasmic reticulum (SR). The magnitude of [Ca2+](i) elevation during stimulation depends on. (a) the rate of Ca2+ release from the SR, (b) the rate of Ca2+ uptake by the SR, and (c) the myoplasmic Ca2+ buffering. We have used fluorescent Ca2+ indicators to measure [Ca2+](i) in intact, single fibres from mouse and Xenopus muscles under conditions where one or more of the above factors are changed. The following interventions resulted in increased tetanic [Ca2+](i): beta-adrenergic stimulation. which potentiates the SR Ca2+ release. application of 2.5-di(tert-butyl)-1,4-benzohydroquinone, which inhibits SR Ca2+ pumps: application of caffeine, which facilitates SR Ca2+ release and inhibits SR Ca2+ uptake: early fatigue, where the rate of SR Ca2+ uptake is reduced: acidosis. which reduces both the myoplasmic Ca2+ buffering and the rate of SR Ca2+ uptake. Reduced tetanic [Ca2+](i) was observed in late fatigue, due to reduced SR Ca2+ release. and in alkalosis, due to increased myoplasmic Ca2+ buffering. Force is monotonically related to [Ca2+](i). but depends also on the myofibrillar Ca2+ sensitivity and the maximum force cross-bridges can produce. This is clearly illustrated by changes of intracellular pH where. despite a lower tetanic [Ca2+](i), tetanic force is higher in alkalosis than acidosis due to increases of myofibrillar Ca2+ sensitivity and maximum cross-bridge force.