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Laboratory of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva, CH 1211 Geneva 4, Switzerland

Correspondence to Urs T. Ruegg: urs.ruegg{at}pharm.unige.ch

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 Ca²⁺ 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_v1.4, 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_v1.4, leading to an increased Na⁺ concentration under the sarcolemma. Moreover, the distribution of Na_v1.4 is altered in mdx muscle while maintaining the colocalization with one of the dystrophin-associated proteins, syntrophin -1, thus suggesting that syntrophin is an important linker between dystrophin and Na_v1.4. Additionally, we show that these modifications of Na_v1.4 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_v1.4 blocker.

Abbreviations used in this paper: DGC, dystrophin–glycoprotein complex; DMD, Duchenne muscular dystrophy; FDB, flexor digitorum brevis; TTX, tetrodotoxin; VGSC, voltage-gated sodium channel.

© 2008 Hirn et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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