Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness
Lawrence J. Hayward, … , Stephen C. Cannon, Robert H. Brown Jr.
Lawrence J. Hayward, … , Stephen C. Cannon, Robert H. Brown Jr.
Published March 3, 2008
Citation Information: J Clin Invest. 2008;118(4):1437-1449. https://doi.org/10.1172/JCI32638.
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Research Article Muscle biology

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

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 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.

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 Jr.

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Figure 7

Mutant (+/m) EDL was more sensitive than control (+/+) muscle to inhibition of force by ouabain (OB), which also exacerbated the weakness produced by elevated [K+]o.

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Mutant (+/m) EDL was more sensitive than control (+/+) muscle to inhibit...
Isolated EDL muscles from 8.9 ± 0.2–month-old mutant mice or sibling controls were equilibrated in bath containing 4 mM [K+]o and 1.3 mM [Ca2+]o and stimulated as in Figure 6; normalized peak tetanic responses (mean ± SEM) are shown. (A) Mutant EDL was highly sensitive to 0.5–2.0 μM ouabain, which affected control muscle much more slowly. (B) Adding 0.5 μM ouabain greatly exacerbated the force reduction caused by raising [K+]o to 8 mM (compare Figure 6B) and produced sustained weakness. (C) Adding 0.5 μM ouabain upon raising [K+]o to 10 mM not only produced rapid paralysis that was reversible in the recovery solution but also nearly abolished the partial rebound that had occurred after 7 minutes in Figure 6C. Gray bars indicate significant differences by ANOVA (P < 0.05) between mutant (red circles) and control (open squares) responses. ANOVA was not determined in A during 40–60 minutes because the ouabain concentration was different for mutant (0 μM) and control (2 μM).