| First Author | Hayward LJ | Year | 2008 |
| Journal | J Clin Invest | Volume | 118 |
| Issue | 4 | Pages | 1437-49 |
| PubMed ID | 18317596 | Mgi Jnum | J:135831 |
| Mgi Id | MGI:3794514 | Doi | 10.1172/JCI32638 |
| Citation | Hayward LJ, et al. (2008) Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness. J Clin Invest 118(4):1437-49 |
| abstractText | 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. |
