Department of Neurology
Aging; Animals; Disease Progression; Electrophysiology; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Muscle, Skeletal; Mutation; Myotonia; Oxidation-Reduction; Paralysis, Hyperkalemic Periodic; Phenotype; Potassium; RNA, Messenger; Sensitivity and Specificity; Sodium Channels
Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
J Clin Invest. 2008 Apr;118(4):1437-49. Link to article on publisher's site
The Journal of clinical investigation
Hayward LJ, Kim JS, Lee M, Zhou H, Kim JW, Misra K, Salajegheh M, Wu F, Matsuda S, Reid V, Cros D, Hoffman EP, Renaud J, Cannon SC, Brown RH. (2008). Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness. Open Access Articles. https://doi.org/10.1172/JCI32638. Retrieved from https://escholarship.umassmed.edu/oapubs/1943