Referenced in: none

Automatically associated channels: Nav1.4 , Slo1

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

Authors: 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

Journal, date & volume: J. Clin. Invest., 2008 Apr , 118, 1437-49

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18317596

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.