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.
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.