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 4

Mutant (+/m) muscles from older mice exhibited mild myopathic changes, a more oxidative fiber type, and upregulation of the transcriptional coactivator PGC-1α.

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Mutant (+/m) muscles from older mice exhibited mild myopathic changes, a...
(A and B) H&E staining of tibialis anterior muscle from a normal (+/+) mouse at 24 months of age exhibited a normal pattern of fiber size variation and peripheral nuclei (A), while that from a mutant (+/m) sibling mouse showed increased fiber size variation and more frequent internalized nuclei (B). (C and D) Succinate dehydrogenase (SDH) staining of serial sections revealed a mixed pattern of oxidative (dark) and glycolytic (light) fibers for tibialis anterior muscle from the normal (+/+) mouse (C), while that from the (+/m) mouse showed an increase of SDH-positive fibers, indicating a more oxidative phenotype (D). (E and F) Immunostaining of serial sections with A4.74 myosin antibody confirmed a large increase in fast oxidative fibers (type IIA) in the mutant (+/m) compared with the normal (+/+) muscle. Scale bars in A–F: 100 μm. (G) Western blot (2 μg of soluble muscle lysate protein per lane as determined by BCA assay) showed increased expression of PGC-1α by 2.1 ± 0.5–fold in tibialis anterior muscle from 1-year-old (+/m) mice compared with controls.