Résumé :
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Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy. The pathology is caused by mutations in the dystrophin gene but the mechanisms linking the absence of dystrophin to the massive muscle necrosis and progressive muscle weakness observed are not yet fully understood. The data accumulated suggest that signaling pathway deregulation may well play a role and we decided to focus on signaling pathways in skeletal muscles, using the Golden Retriever Muscular Dystrophy (GRMD) dog that has a pathophysiology reminiscent of that of human DMD. Antibody array analysis revealed a reduction in the phosphorylation of kinases in the PI3K/Akt and ERK signaling pathways in dystrophic when compared to healthy muscles. Analysis of the compartment-specific location of Akt indicated that this kinase, despite displaying moderately increased expression, exhibited less susceptibility to being bound to the plasma membrane and then being translocated into the nucleus. We found that low Akt phosphorylation was associated with increased expression of PTEN and PP2A phosphatases. The reduced amount of phosphorylated Akt affects downstream located pathways, as we observed decreased phosphorylation of both p70S6K and GSK3b kinases. Moreover, the amount of the non-phosphorylated and active form of GSK3b was elevated in dystrophic muscles. Decreased phosphorylation of ERK1 and ERK2 kinases was also demonstrated. Altogether, these findings suggest that the abnormalities identified in signaling pathways might lead to an imbalance between protein synthesis and protein degradation, thereby contributing to the complex physiopathological process observed in the GRMD dog.
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