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

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Jun 30, 2021 version files 229.02 KB
Jan 06, 2022 version files 259.85 KB

Abstract

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. Intracellular recordings of action potentials (APs) in individual mouse skeletal muscle fibers during depolarization of the resting potential revealed small APs are still generated at resting potentials at which force production has failed. Simultaneous imaging of Ca2+ transients and recording of APs demonstrated failure to generate Ca2+ transients when APs peaked at potentials more negative than -30 mV. An AP property that closely correlated with failure of the Ca2+ transient was the integral of AP voltage with respect to time. Simultaneous recording of Ca2+ transients and APs with electrodes separated by 1.6 mm revealed AP conduction fails when APs peak below -21 mV. We hypothesize propagation of APs and generation of Ca2+ transients are governed by distinct AP properties: AP conduction is governed by AP peak, whereas Ca2+ release from the sarcoplasmic reticulum is governed by AP integral of voltage with respect to time. The reason distinct AP properties may govern separate steps of ECC is the kinetics of the ion channels involved in the different steps of ECC. Na channels, which govern propagation, have rapid kinetics such that propagation is insensitive to AP width (and integral) whereas Ca2+ release is governed by movement of gating charges in Cav1.1 channels, which have slower kinetics such that Ca2+ release is sensitive to AP width (and integral). The quantitative relationships established between resting potential, AP properties, AP conduction and Ca2+ transients provide the foundation for future studies of failure of ECC induced by depolarization of the resting potential.