GSE97019
Activation of the interferon type I response rather than autophagy contributes to myogenesis inhibition in congenital DM1 myoblasts
Congenital Myotonic Dystrophy type 1 (CDM1) is characterized by severe symptoms that affect patients from birth, with 40% mortality in the neonatal period and impaired skeletal muscle development. In this paper, we examined the relationship between autophagy and abnormal myogenic differentiation of CDM1 myoblasts. We investigated these pathological features at both ultrastructural and molecular levels, utilizing two CDM1 foetal myoblasts, CDM13 and CDM15, with 1800 and 3200 repeats respectively. The congenital nature of these CDM1 myoblasts was confirmed by the high methylation level at the DMPK locus. Our results indicated that abnormal autophagy was independent of myogenic differentiation as CDM13 myoblasts differentiated as well as control myoblasts but underwent autophagy like CDM15 displaying impaired differentiation. miRNA expression profiles revealed that CDM15 myoblasts failed to upregulate the complex network of myo-miRNAs under MYOD and MEF2A control while this network was upregulated in CDM13 myoblasts. Interestingly, the abnormal differentiation of CDM15 myoblasts was associated with cellular stress accompanied by the induction of the interferon type 1 pathway (innate immune response). Indeed, inhibition the IFN type I pathway restores myogenic differentiation of CDM15 myoblasts suggesting that the inappropriate activation of the innate immune response might contribute to impaired myogenic differentiation and severe muscle symptoms observed in some CDM1 patients. These findings open up the possibility of new therapeutic approaches to treat CDM1. Overall design: miRNA profiing of two CDM1 fetal myoblasts carryng different numbers of triplets (MCBO and DM15Q with 1800 and 3200 repeats, respectively).  12,000 cells/cm2 were grown in HAM'S/F10 medium with 50 µg/ml Fetuin, 5 µg/ml Insulin, 0.5 mg/ml BSA and 20% FBS to subconflence.  Subconfluent cells were shifted to differentiation medium (MEM with 10 µg/ml, insulin, 10 ng/ml EGF and 0.5 mg/ml BSA) were samples at day 0 and day 3.  Two replicates per sample.