Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness.
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.
Hayward
Lawrence J
LJ
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. lawrence.hayward@umassmed.edu
Kim
Joanna S
JS
Lee
Ming-Yang
MY
Zhou
Hongru
H
Kim
Ji W
JW
Misra
Kumudini
K
Salajegheh
Mohammad
M
Wu
Fen-fen
FF
Matsuda
Chie
C
Reid
Valerie
V
Cros
Didier
D
Hoffman
Eric P
EP
Renaud
Jean-Marc
JM
Cannon
Stephen C
SC
Brown
Robert H
RH
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*
D012333:RNA, Messenger; D015222:Sodium Channels; D011188:Potassium