Résumé :
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Duchenne muscular dystrophy (DMD) is a fatal muscle disorder caused by the absence of dystrophin and characterized by progressive muscle wasting. Oxidative stress and excessive calcium influx are thought to contribute to the pathogenesis. Indeed, we have previously shown that dietary interventions with powerful antioxidants such as green tea polyphenols (GTP) and EGCG (the major GTP component) improved muscle structure and function of the mdx5Cv mouse, a model for DMD. As clinical trials are being conducted with EGCG on DMD patients, we report additional therapeutic effects of GTP and EGCG on the dystrophic mouse. As in our previous study, 3-week old mice were given for 5 to 8 weeks a chow enriched with GTP, EGCG or pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor and TNF_ release inhibitor used as a positive control. Prednisolone (PDN) was also tested alone or in combination with EGCG. GTP, EGCG, and PTX ameliorated spontaneous locomotor activity and performance in a wheel running assay, and decreased plasma creatine kinase levels (a marker of muscle membrane fragility). The manganese quench technique was used to measure the influx of calcium into muscle fibers isolated from FDB muscles and loaded with the calcium probe Fura-2. Treatment of the mice with GTP, EGCG, or PTX reduced by up to two-thirds the excessive calcium influx in dystrophic muscle fibres in resting conditions. Acute exposure to these agents had no effect. Similar findings were obtained from diaphragm strips in 45Ca2+ influx experiments. Overall, PDN was less potent than EGCG and tended to obscure the beneficial effects afforded by EGCG when given in combination. The expression levels of candidate calcium channels and calcium binding proteins are being determined at the protein and mRNA level. Our findings suggest that GTP, EGCG, and PTX act through genome-dependent mechanisms to decrease the expression and/or the activity of calcium channels overactive in dystrophic cells. This effect likely contributes to the overall improvement of motor function on the awaken animal.
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