Nav1.4 deregulation in dystrophic skeletal muscle leads to Na+ overload and enhanced cell death.
Duchenne muscular dystrophy (DMD) is a hereditary degenerative disease manifested by the absence of dystrophin, a structural, cytoskeletal protein, leading to muscle degeneration and early death through respiratory and cardiac muscle failure. Whereas the rise of cytosolic Ca(2+) concentrations in muscles of mdx mouse, an animal model of DMD, has been extensively documented, little is known about the mechanisms causing alterations in Na(+) concentrations. Here we show that the skeletal muscle isoform of the voltage-gated sodium channel, Na(v)1.4, which represents over 90% of voltage-gated sodium channels in muscle, plays an important role in development of abnormally high Na(+) concentrations found in muscle from mdx mice. The absence of dystrophin modifies the expression level and gating properties of Na(v)1.4, leading to an increased Na(+) concentration under the sarcolemma. Moreover, the distribution of Na(v)1.4 is altered in mdx muscle while maintaining the colocalization with one of the dystrophin-associated proteins, syntrophin alpha-1, thus suggesting that syntrophin is an important linker between dystrophin and Na(v)1.4. Additionally, we show that these modifications of Na(v)1.4 gating properties and increased Na(+) concentrations are strongly correlated with increased cell death in mdx fibers and that both cell death and Na(+) overload can be reversed by 3 nM tetrodotoxin, a specific Na(v)1.4 blocker.
Hirn
Carole
C
Laboratory of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva, CH 1211 Geneva 4, Switzerland.
Shapovalov
George
G
Petermann
Olivier
O
Roulet
Emmanuelle
E
Ruegg
Urs T
UT
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D015640:Ion Channel Gating; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D062553:NAV1.4 Voltage-Gated Sodium Channel; D012508:Sarcolemma / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
D016189:Dystrophin; D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; C491391:Scn4a protein, mouse; D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium