Résumé :
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Daily treatment of adult mdx mice with intraperitoneal injections of pyrrolidine dithiocarbamate (PDTC) substantially improved the resting membrane potential in severely dystrophic (mdx) triangularis sterni (TS) muscle fibers (Carlson et al., Neurobiology of Disease , 20 (3), 719-730, 2005). To determine whether this effect was mediated by circulating factors exogenous to skeletal muscle, the effect of PDTC on the resting potential of freshly excised triangularis sterni (TS) muscle fibers was examined in vitro. Although PDTC had no effect on the resting potential of nondystrophic fibers, 100 ?M PDTC produced a significant -6.9 mV increase in the average resting potential of mdx TS fibers (7.5 month, caudal region) over a 90 minute interval. Pre-treatment with ouabain abolished this restorative effect of PDTC on the resting potential of mdx fibers. To determine the contribution of the Na+ - K+ ATPase on the resting membrane potential, nondystrophic and mdx fibers were exposed to 10-3 M ouabain for 30 minutes. The reduction in resting potential produced by ouabain in mdx TS fibers (+4.3 mV) was significantly and substantially less than that observed in nondystrophic TS fibers (+14.7 mV). Fluorimetric determinations (F340/F380) in SBFI loaded muscle fibers also suggested that intracellular Na+ is elevated in mdx TS fibers. Consistent with the resting potential measurements, the increase in F340/F380 induced by ouabain in nondystrophic fibers was substantially and significantly greater than that observed in mdx fibers. These results suggest that: (1) the reduced resting potentials in dystrophic muscle are associated with altered Na+-K+ pump activity, increases in intracellular Na+, and a reduction in the outward Na+ pump current; and (2) PDTC improves the resting potential by a direct or indirect effect on Na+-K+ pump activity. (Supported by AFM, Charley’s Fund, Strategic Research Grant from ATSU)
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