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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/65691 |
| _version_ | 1828169113112936448 |
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| 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 |
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