The mechanism underlying transient weakness in myotonia congenita.

Jessica H Myers,Andrew Koesters,Chris Dupont,Mark M Rich,Ahmed A Hawash,Anamika Dayal,Kirsten Denman,Kevin R Novak,Manfred Grabner,Andrew A Voss

doi:10.7554/elife.65691

Jessica H Myers, Andrew Koesters + Show 8 more

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https://doi.org/10.7554/elife.65691

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Abstract

In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to -25 to -35 mV in the genetic and pharmacologic models of Becker disease. Both Na+ and Ca2+ currents contribute to plateau potentials. Na+ persistent inward current (NaPIC) through NaV1.4 channels is the key trigger of plateau potentials and current through CaV1.1 Ca2+ channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenita.

Highlights

Myotonia congenita is one of the non-dystrophic muscle channelopathies
We previously found that ranolazine was effective in eliminating myotonia by blocking Na+ persistent inward current (NaPIC) while sparing enough fast-inactivating Na+ channels to allow for repetitive firing of action potentials triggered by current injection (Novak et al, 2015; Hawash et al, 2017)
Using intracellular recordings from a mouse model of myotonia congenita (ClCadr), we discovered that while some runs of myotonia resolved with repolarization, others terminated with a plateau potential; that is, depolarization to a membrane potential between À30 and À45 myotonia vm (mV), lasting up to 100 s

Summary

Introduction

Myotonia congenita is one of the non-dystrophic muscle channelopathies. It is caused by loss-offunction mutations affecting the muscle chloride channel (ClC-1) (Lipicky et al, 1971; Steinmeyer et al, 1991; Koch et al, 1992). There appears to be loss of muscle excitability, as weakness is accompanied by a drop in compound muscle action potential (CMAP) amplitude during repetitive stimulation (Ricker and Meinck, 1972; Brown, 1974; Aminoff et al, 1977; Deymeer et al, 1998; Drost et al, 2001; Modoni et al, 2011) This drop in CMAP is associated with reduction in muscle fiber conduction velocity, which has been proposed to progress to depolarization block (Zwarts and van Weerden, 1989). Perhaps counterintuitive, is why a loss-of-function mutation of the muscle ClC-1 channels in myotonia

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