Résumé :
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Duchenne Muscular dystrophy (DMD) is manifested by the absence of dystrophin – a structural, cytoskeletal protein – leading to muscle degeneration. Whereas the rise of cytosolic Ca2+ concentration has been extensively documented in the muscle of mdx mouse, little is known about alterations of Na+ concentration. We observed that 22Na+ influx is elevated in mdx FDB muscle and tetrodotoxin (TTX 3nM) an inhibitior of voltage-gated sodium channels restored Na+ influx in mdx to that of control fibers without affecting the latter. Here we show, for the first time, that the skeletal isoform of VGSC, namely Nav1.4, which represents over 90% of VGSCs in muscle, is responsible for abnormal Na+ concentrations found in muscle from mdx mice. The absence of dystrophin modifies the expression level and gating properties of Nav1.4 leading to an increased level of [Na+] under the sarcolemma. Indeed, we observed a reduced inactivation rate and a reduction of the reversal potential for Na+ by 18 mV, indicating an about 2-fold higher [Na+] under sarcolemma in mdx fibres as compared to those of control. Moreover we observed that Nav1.4 colocalized with ?1-syntrophins belonging to dystrophin-associated protein complex and the distribution of both proteins was altered in dystrophin-deficient fibers. To supplement these findings, we studied the survival of mdx and control fibers in culture and found an approximately 30% higher mortality rate of dystrophic fibers. Nav1.4 inhibition with tetrodotoxin improved survival of mdx isolated fibers in culture close to the one of control fibers over a period of 3 days. These results suggest that modifications of Nav1.4 properties and excess Na+ strongly correlate with increased cell death in mdx fibres.
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