Absence of a differentiation defect in muscle satellite cells from DM2 patients

Myotonic dystrophy type 1 (DM1) and type II (DM2) are dominantly inherited multisystemic disorders. DM1 is triggered by the pathological expansion of a (CTG)(n) triplet repeat in the DMPK gene, whereas a (CCTG)(n) tetranucleotide repeat expansion in the ZNF9 gene causes DM2. Both forms of the disease share several features, even though the causative mutations and the loci involved differ. Important distinctions exist, such as the lack of a congenital form of DM2. The reason for these disparities is unknown. In this study, we characterized skeletal muscle satellite cells from adult DM2 patients to provide an in vitro model for the disease. We used muscle cells from DM1 biopsies as a comparison tool. Our main finding is that DM2 satellite cells differentiate normally in vitro. Myotube formation was similar to unaffected controls. In contrast, fetal DM1 cells were deficient in that ability. Consistent with this observation, the myogenic program in DM2 was intact but is compromised in fetal DM1 cells. Although expression of the ZNF9 gene was enhanced in DM2 during differentiation, the levels of the ZNF9 protein were substantially reduced. This suggests that the presence of a large CCTG tract impairs the translation of the ZNF9 mRNA. Additionally, DM2 muscle biopsies displayed the altered splicing of the insulin receptor mRNA, correlating with insulin resistance in the patients. Finally, CUGBP1 steady-state protein levels were unchanged in DM2 cultured muscle cells and in DM2 muscle biopsies relative to controls, whereas they are increased in DM1 muscle cells. Our findings suggest that the myogenic program throughout muscle development and tissue regeneration is intact in DM2.