Résumé :
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Duchenne's muscular dystrophy (DMD) is a genetic muscle disorder that affects muscle fiber integrity. Cyclic phases of degeneration and regeneration eventually lead to necrosis and replacement of muscle with fibrotic tissue. The molecular events that attribute to the dystrophic phenotype in DMD have not been fully elucidated. One mechanism known to be involved is the kinase JNK. Kinase assays revealed elevated JNK activity in dystrophic (MDX) muscle compared to WT muscle. Similarly, the RhoGTPase TC10 may also be involved as we observed elevated TC10 activity in dystrophic (MDX) muscle compared to WT muscle. Previous studies have shown that both JNK and TC10 interact with specific components of the insulin signaling pathway and thus influence glucose metabolism. Interestingly, glucose metabolism has been reported to be altered in DMD patients. In the present study we investigated the expression pattern of proteins within the insulin signaling pathway in the murine (MDX) model of Duchenne's muscular dystrophy. Our observations revealed that in dystrophic (MDX) muscle, phosphorylation of the IRS-1 substrate at tyrosine941, which is an essential requirement for normal insulin signaling, was decreased. In contrast phosphorylation of the IRS-1 substrate on serine307, which is affiliated with insulin resistance, was elevated. Moreover, JNK phosphorylates the IRS-1 substrate at serine307. Further downstream the insulin signaling pathway, translocation of GLUT4 to the plasma membrane facilitates glucose transport in response to insulin. Immunohistochemistry revealed that normal GLUT4 translocation was perturbed, as GLUT4 remained localized predominantly in the cytoplasm in dystrophic (MDX) muscle. However, GLUT4 remained primarily along the periphery of the plasma membrane in (WT) muscle. Additionally, PAS staining revealed an accumulation of glycogen levels in dystrophic muscle compared to WT muscle. These results suggest that perturbations in the insulin signaling pathway may contribute to the dystrophic phenotype.
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