title: 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 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.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. lawrence.hayward@umassmed.edu
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Hayward
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Kim
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Lee
authors.forename: Hongru
authors.initials: H
authors.lastname: Zhou
authors.forename: Ji W
authors.initials: JW
authors.lastname: Kim
authors.forename: Kumudini
authors.initials: K
authors.lastname: Misra
authors.forename: Mohammad
authors.initials: M
authors.lastname: Salajegheh
authors.forename: Fen-fen
authors.initials: FF
authors.lastname: Wu
authors.forename: Chie
authors.initials: C
authors.lastname: Matsuda
authors.forename: Valerie
authors.initials: V
authors.lastname: Reid
authors.forename: Didier
authors.initials: D
authors.lastname: Cros
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Renaud
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cannon
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D018450:Disease Progression; D004594:Electrophysiology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009222:Myotonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction; D020513:Paralysis, Hyperkalemic Periodic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011188:Potassium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012680:Sensitivity and Specificity; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D015222:Sodium Channels; D011188:Potassium