Résumé :
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Myotonic Dystrophy type 1 (DM1), one of the most common forms of inherited neuromuscular disorders, is caused by a (CTG)n>40 repeat expansion in the 3'non-coding region of the DMPK gene. DM1 is an RNA-dominant disorder due to the expression of mutant DMPK transcripts containing CUG expansions (CUGexp-RNA) and is characterized by myotonia, progressive muscle weakness and wasting. In addition, a severe congenital form of DM1 is associated with hypotonia, delayed muscle maturation and large (CTG)n expansions (n>1500). We have previously shown that the myogenic program of the myoblasts isolated from congenital DM1 (cDM1) muscles is altered: differentiation is impaired and proliferative capacity is significantly reduced when compared to non-affected cells. The cDM1 myoblasts showed a premature replicative arrest and a mechanism of premature senescence triggers this early proliferative arrest. Our results demonstrate that an early activation of the p16 stress pathway is responsible for this defect: inactivation of the p16 cyclin dependent kinase inhibitor in cDM1 myoblasts inhibits premature senescence and restores their proliferative capacity. The mechanism directly implicated in this abnormal activation of the p16 stress sensor pathway in cDM1 cells is currently under investigation. Involvement of cellular redox modifications in cells expressing expanded CTG repeats is also being examined since low-oxygen conditions have been shown to increase the proliferative capacity of cDM1 cells and delay activation of p16 in these cells. In addition an increased susceptibility to oxidative stress is observed in cDM1 compared to control myoblasts.
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