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Immunolabelling Myofiber Degeneration in Muscle Biopsies
Published on: December 5, 2019
Leaky channels make weak muscles
1Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA. al.george@vanderbilt.edu
Abstract:
Mutations in the skeletal muscle voltage-gated calcium channel (CaV1.1) have been associated with hypokalemic periodic paralysis, but how the pathogenesis of this disorder relates to the functional consequences of mutations was unclear. In this issue of the JCI, Wu and colleagues recapitulate the disease by generating a novel knock-in CaV1.1 mutant mouse and use this model to investigate the cellular and molecular features of pathogenesis. They demonstrated an aberrant muscle cell current conducted through the CaV1.1 voltage-sensor domain (gating pore current) that explains an abnormally depolarized muscle membrane and the failure of muscle action potential firing during challenge with agents known to provoke periodic paralysis. Their work advances understanding of molecular and cellular mechanisms underlying an inherited channelopathy.
Insights
Mutations in the skeletal muscle calcium channel (CaV1.1) cause hypokalemic periodic paralysis. A new mouse model reveals aberrant gating pore currents, explaining muscle membrane depolarization and paralysis.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Mutations in the skeletal muscle voltage-gated calcium channel (CaV1.1) are linked to hypokalemic periodic paralysis.
- The precise relationship between CaV1.1 mutations and the disorder's pathogenesis remained unclear.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms underlying hypokalemic periodic paralysis caused by CaV1.1 mutations.
- To establish a CaV1.1 mutant mouse model that recapitulates the disease.
Main Methods:
- Generation of a novel knock-in CaV1.1 mutant mouse model.
- Electrophysiological analysis of muscle cell currents and membrane potential.
- Investigation of molecular features of pathogenesis during paralysis provocation.
Main Results:
- Demonstrated aberrant muscle cell current (gating pore current) conducted through the CaV1.1 voltage-sensor domain.
- Explained abnormally depolarized muscle membrane potential in the mutant model.
- Showed failure of muscle action potential firing during paralysis provocation.
Conclusions:
- Aberrant gating pore currents in CaV1.1 are a key mechanism in hypokalemic periodic paralysis pathogenesis.
- The CaV1.1 mutant mouse model provides insights into inherited channelopathies.
- Advances understanding of molecular and cellular mechanisms underlying muscle channelopathies.
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