Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

Lawrence J. Hayward, Joanna S. Kim, Ming Yang Lee, Hongru Zhou, Ji W. Kim, Kumudini Misra, Mohammad Salajegheh, Fen Fen Wu, Chie Matsuda, Valerie Reid, Didier Cros, Eric P. Hoffman, Jean Marc Renaud, Stephen C. Cannon, Robert H. Brown

Research output: Contribution to journalArticle

38 Scopus citations

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 Na V1.4. 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 Met1592Val Na + 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.

Original languageEnglish (US)
Pages (from-to)1437-1449
Number of pages13
JournalJournal of Clinical Investigation
Volume118
Issue number4
DOIs
StatePublished - Apr 1 2008

ASJC Scopus subject areas

  • Medicine(all)

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    Hayward, L. J., Kim, J. S., Lee, M. Y., Zhou, H., Kim, J. W., Misra, K., Salajegheh, M., Wu, F. F., Matsuda, C., Reid, V., Cros, D., Hoffman, E. P., Renaud, J. M., Cannon, S. C., & Brown, R. H. (2008). Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness. Journal of Clinical Investigation, 118(4), 1437-1449. https://doi.org/10.1172/JCI32638