The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle

Excitation-contraction coupling (ECC) is the process by which electrical excitation of muscle is converted into force generation. Depolarization of skeletal muscle resting potential contributes to failure of ECC in diseases such as periodic paralysis, intensive care unit acquired weakness and possibly fatigue of muscle during vigorous exercise. When extracellular K(+) is raised to depolarize the resting potential, failure of ECC occurs suddenly, over a narrow range of resting potentials. Simultaneous imaging of Ca(2+) transients and recording of action potentials (APs) demonstrated failure to generate Ca(2+) transients when APs peaked at potentials more negative than –30mV. An AP property that closely correlated with failure of the Ca(2+) transient was the integral of AP voltage with respect to time. Simultaneous recording of Ca(2+) transients and APs with electrodes separated by 1.6mm revealed AP conduction fails when APs peak below –21mV. We hypothesize propagation of APs and generation of Ca(2+) transients are governed by distinct AP properties: AP conduction is governed by AP peak, whereas Ca(2+) release from the sarcoplasmic reticulum is governed by AP integral. The reason distinct AP properties may govern distinct steps of ECC is the kinetics of the ion channels involved. Na channels, which govern propagation, have rapid kinetics and are insensitive to AP width (and thus AP integral) whereas Ca(2+) release is governed by gating charge movement of Cav1.1 channels, which have slower kinetics such that Ca(2+) release is sensitive to AP integral. The quantitative relationships established between resting potential, AP properties, AP conduction and Ca(2+) transients provide the foundation for future studies of failure of ECC induced by depolarization of the resting potential.