Résumé :
|
Communication n° 332 Myotonic dystrophy (DM1) is a neuromuscular disease caused by the expansion of a trinucleotide repeat (CTG) located in the 3'UTR of the DMPK gene. Impairment in skeletal muscle development represents one of the main features in the congenital form of DM1 (CDM) that is associated with large expansions (CTG > 1500). We have previously shown that the differentiation program of the satellite cells isolated from the CDM muscles is defective. Interestingly, the proliferative capacity of the CDM myoblasts was also reduced when compared to normal cells. As for other human somatic cells, the proliferative capacity of the human myoblasts is limited by a mitotic clock determined by the telomere length. However we showed that the premature arrest of CDM myoblasts is not correlated with an excessive reduction of the telomere length since the CDM myoblasts stop dividing with larger telomeric DNA restriction fragments than control myoblasts (8,7 vs 7,2 kb). This result clearly indicates that the CDM myoblasts have not exhausted their proliferative capacity (as an example, DMD myoblasts do exhaust their proliferative capacity due to repeated rounds of degeneration/regeneration). We also observed that the p16 pathways involved in cell cycle arrest of senescent control cells is also activated in CDM myoblasts with premature arrest. Thus the presence of large CTG mutation may be toxic for the cells and leads to a cellular stress that triggered a premature senescence in CDM myoblasts. We propose that the effect of the large CTG mutation, such as mitotic instability of the CTG expansion and/or nuclear aggregates of mutant DMPK transcripts with large CUG expansions, may induce a telomere-independent mechanism leading to the early replicative arrest of CDM myoblasts via the induction of a senescence-like program.
|