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.
Rights and Permissions
Citation: J Clin Invest. 2008 Apr;118(4):1437-49. Link to article on publisher's site