Defective satellite cells in congenital myotonic dystrophy

In this study we have developed an in vitro cell culture system which displ ays the majority of the defects previously described for congenital myotoni c dystrophy (CDM) muscle in vivo. Human satellite cells were isolated from the quadriceps muscles of three CDM fetuses with different clinical severit y. By Southern blot analysis all three cultures were found to have approxim ately 2300 CTG repeats. This CTG expansion was found to progressively incre ase in size during the proliferative life span, confirming an instability o f this triplet in skeletal muscle cells. The CDM myoblasts and myotubes als o showed abnormal retention of mutant RNA in nuclear foci, as well as modif ications in their myogenic program. The proliferative capacity of the CDM m yoblasts was reduced and a delay in fusion, differentiation and maturation was observed in the CDM cultures compared with unaffected myoblast cultures . The clinical severity and delayed maturation observed in the CDM fetuses were closely reflected by the phenotypic modifications observed in vitro. S ince the culture conditions were the same, this suggests that the defects w e have described are intrinsic to the program expressed by the myoblasts in the absence of any trophic factors. Altogether, our results demonstrate th at satellite cells are defective in CDM and are probably implicated in the delay in maturation and muscle atrophy that has been described previously i n CDM fetuses.