The mechanism underlying transient weakness in myotonia congenita

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 mous...

Full beskrivning

Bibliografiska uppgifter
Huvudupphovsmän: Jessica H Myers, Kirsten Denman, Chris DuPont, Ahmed A Hawash, Kevin R Novak, Andrew Koesters, Manfred Grabner, Anamika Dayal, Andrew A Voss, Mark M Rich
Materialtyp: Artikel
Språk:English
Publicerad: eLife Sciences Publications Ltd 2021-04-01
Serie:eLife
Ämnen:
Länkar:https://elifesciences.org/articles/65691
_version_ 1828169113112936448
author Jessica H Myers
Kirsten Denman
Chris DuPont
Ahmed A Hawash
Kevin R Novak
Andrew Koesters
Manfred Grabner
Anamika Dayal
Andrew A Voss
Mark M Rich
author_facet Jessica H Myers
Kirsten Denman
Chris DuPont
Ahmed A Hawash
Kevin R Novak
Andrew Koesters
Manfred Grabner
Anamika Dayal
Andrew A Voss
Mark M Rich
author_sort Jessica H Myers
collection DOAJ
description 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.
first_indexed 2024-04-12T02:45:51Z
format Article
id doaj.art-f201e13c4e5f4c20b08b45b730d90c95
institution Directory Open Access Journal
issn 2050-084X
language English
last_indexed 2024-04-12T02:45:51Z
publishDate 2021-04-01
publisher eLife Sciences Publications Ltd
record_format Article
series eLife
spelling doaj.art-f201e13c4e5f4c20b08b45b730d90c952022-12-22T03:51:10ZengeLife Sciences Publications LtdeLife2050-084X2021-04-011010.7554/eLife.65691The mechanism underlying transient weakness in myotonia congenitaJessica H Myers0Kirsten Denman1Chris DuPont2Ahmed A Hawash3Kevin R Novak4Andrew Koesters5https://orcid.org/0000-0003-3281-188XManfred Grabner6https://orcid.org/0000-0002-5196-4024Anamika Dayal7https://orcid.org/0000-0001-8075-8812Andrew A Voss8Mark M Rich9https://orcid.org/0000-0002-6956-5531Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United StatesDepartment of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United StatesDepartment of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United StatesDepartment of Dermatology & Cutaneous Surgery, University of Miami, Miami, United StatesEvokes LLC, Mason, United StatesNaval Medical Research Unit, Wright Patterson Air Force Base, Dayton, United StatesDepartment of Pharmacology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Pharmacology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Biology, Wright State University, Dayton, United StatesDepartment of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, United StatesIn 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.https://elifesciences.org/articles/65691muscle fibermyotoniasodium channelcalcium channelpersistent sodium currentexcitability
spellingShingle Jessica H Myers
Kirsten Denman
Chris DuPont
Ahmed A Hawash
Kevin R Novak
Andrew Koesters
Manfred Grabner
Anamika Dayal
Andrew A Voss
Mark M Rich
The mechanism underlying transient weakness in myotonia congenita
eLife
muscle fiber
myotonia
sodium channel
calcium channel
persistent sodium current
excitability
title The mechanism underlying transient weakness in myotonia congenita
title_full The mechanism underlying transient weakness in myotonia congenita
title_fullStr The mechanism underlying transient weakness in myotonia congenita
title_full_unstemmed The mechanism underlying transient weakness in myotonia congenita
title_short The mechanism underlying transient weakness in myotonia congenita
title_sort mechanism underlying transient weakness in myotonia congenita
topic muscle fiber
myotonia
sodium channel
calcium channel
persistent sodium current
excitability
url https://elifesciences.org/articles/65691
work_keys_str_mv AT jessicahmyers themechanismunderlyingtransientweaknessinmyotoniacongenita
AT kirstendenman themechanismunderlyingtransientweaknessinmyotoniacongenita
AT chrisdupont themechanismunderlyingtransientweaknessinmyotoniacongenita
AT ahmedahawash themechanismunderlyingtransientweaknessinmyotoniacongenita
AT kevinrnovak themechanismunderlyingtransientweaknessinmyotoniacongenita
AT andrewkoesters themechanismunderlyingtransientweaknessinmyotoniacongenita
AT manfredgrabner themechanismunderlyingtransientweaknessinmyotoniacongenita
AT anamikadayal themechanismunderlyingtransientweaknessinmyotoniacongenita
AT andrewavoss themechanismunderlyingtransientweaknessinmyotoniacongenita
AT markmrich themechanismunderlyingtransientweaknessinmyotoniacongenita
AT jessicahmyers mechanismunderlyingtransientweaknessinmyotoniacongenita
AT kirstendenman mechanismunderlyingtransientweaknessinmyotoniacongenita
AT chrisdupont mechanismunderlyingtransientweaknessinmyotoniacongenita
AT ahmedahawash mechanismunderlyingtransientweaknessinmyotoniacongenita
AT kevinrnovak mechanismunderlyingtransientweaknessinmyotoniacongenita
AT andrewkoesters mechanismunderlyingtransientweaknessinmyotoniacongenita
AT manfredgrabner mechanismunderlyingtransientweaknessinmyotoniacongenita
AT anamikadayal mechanismunderlyingtransientweaknessinmyotoniacongenita
AT andrewavoss mechanismunderlyingtransientweaknessinmyotoniacongenita
AT markmrich mechanismunderlyingtransientweaknessinmyotoniacongenita