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- Title
Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness.
- Authors
Hayward, Lawrence J.; Kim, Joanna S.; Ming-Yang Lee; Hongru Zhou; Kim, Ji W.; Misra, Kumudini; Salajegheh, Mohammad; Fen-fen Wu; Matsuda, Chie; Reid, Valerie; Cros, Didier; Hoffman, Eric P.; Renaud, Jean-Marc; Cannon, Stephen C.; Brown Jr., Robert H.; Lee, Ming-Yang; Zhou, Hongru; Wu, Fen-fen; Brown, Robert H Jr
- Abstract
Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K+ ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na+ channel NaV1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fiber-type switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na+/K+ pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness of isolated mutant muscles was induced when the extracellular K+ concentration was increased from 4 mM to 10 mM, a level observed in the muscle interstitium of humans during exercise. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, and the extent of recovery was decreased in the presence of high extracellular K+ levels. These findings demonstrate that expression of the Met1592ValNa+ channel in mouse muscle is sufficient to produce important features of HyperKPP, including myotonia, K+-sensitive paralysis, and susceptibility to delayed weakness during recovery from fatigue.
- Subjects
MUSCLES; GENETIC mutation; LABORATORY mice; SODIUM channels; MYOTONIA; POTASSIUM metabolism; AGING; ANIMAL experimentation; COMPARATIVE studies; ELECTROPHYSIOLOGY; GENES; RESEARCH methodology; MEDICAL cooperation; MEMBRANE proteins; MICE; OXIDATION-reduction reaction; RESEARCH; RESEARCH funding; RNA; PHENOTYPES; EVALUATION research; DISEASE progression; SKELETAL muscle
- Publication
Journal of Clinical Investigation, 2008, Vol 118, Issue 4, p1437
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI32638