Résumé :
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Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adult. One characteristic of DM1 is the presence of a congenital form (CDM1), which is almost exclusively of maternal origin. It is the most severe form of DM1 with high neonatal mortality. The phenotype of the CDM1 differs in several aspects from that observed in the adult form and histological examination of skeletal muscles revealed that the changes are those of a failure of development of muscles rather than an active degeneration. To date, little is known about the mechanisms by which the expansion causes the delay in CDM1 muscle development. We recently identified prostaglandin-E2 (PGE-2), as a soluble factor produced specifically by CMD1 myoblasts, which blocks myogenic differentiation. The level of Cox-2 is specifically increased in skeletal muscle derived from CDM1 but not from DM1 or DM2. Treatment of normal myoblasts with PGE-2 blocked their differentiation in a dose-dependant manner. Because COX-2 inhibition also alters cellular production of other PGs, we targeted microsomal PGES (mPGES-1), an enzyme that acts downstream of COX-2 and that affect PGE2 production only. Inhibition of mPGES-1 by specific shRNAs completely abolished the production of PGE2 in the culture medium and restores the ability of CDM1 myoblasts to fuse. The literature describes several molecules that block the synthesis of PGE-2 and are thus candidates to correct the CDM1 phenotype. Among these molecules, acetylsalicylic acid, which is known to act as inhibitors of cyclo-oxygenase enzymes, restores myoblast differentiation. This drug has already received regulatory approval for treatment, making phase 2 and 3 clinical trials possible.
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