Recapitulating muscle disease phenotypes with myotonic dystrophy 1 iPS cells: a tool for disease modeling and drug discovery

Abstract

Myotonic Dystrophy 1 (DM1) is a multi-system disorder primarily affecting the central nervous system, heart and skeletal muscle. It is caused by an expansion of the CTG trinucleotide repeats in the 3’ untranslated region of the DMPK gene. Although patient myoblasts have been used for studying the disease in vitro, the invasiveness as well as the low accessibility to muscle biopsies motivate the development of alternative reliable myogenic models. Here, we established two DM1 iPS cell lines from patient-derived fibroblasts, and using the PAX7 conditional expression system, differentiated these into myogenic progenitors, and subsequently, terminally differentiated myotubes. Both DM1 myogenic progenitors and myotubes were found to express the intranuclear RNA foci exhibiting sequestration of MBNL1. Moreover, we found the DM1-related mis-splicing, namely BIN1 exon 11 in DM1 myotubes. We use this model to test a specific therapy, antisense oligonucleotide treatment, and find that this efficiently abolished RNA foci and rescued BIN1 mis-splicing in DM1 iPS cell-derived myotubes. Together, our results demonstrate that myotubes derived from DM1 iPS cells recapitulate the critical molecular features of DM1 and are sensitive to ASO treatment, confirming that these cells can be used for in vitro disease modeling and candidate drug testing or screening.