Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy.

The common form of myotonic dystrophy (DM1) is associated with the expression of expanded CTG DNA repeats as RNA (CUG-RNA). One idea for how this disease disrupts muscles is that the CUG-RNA is toxic because it binds up and in essence occupies the muscleblind 1 (MBNL1) protein, a key alternative splicing regulator in muscles. To test this idea, we compared the skeletal muscle of two mouse models of DM1, one expressing a CuG-RNA in their muscle and another missing their (MBNL1) genes altogether. Near identity in the abnormal splicing changes suggests that binding of MBNL1 by CUG-RNA explains >80% of the splicing pathology due to CUG-RNA toxicity. In contrast, only about half of abnormal amounts of mRNA in the CUG-RNA muscle are found when MBNL1 is deleted, indicating that CUG-RNA has effects through another protein, in particular on mRNAs for the extracellular matrix proteins that are so important for muscle structure and function. We propose that CUG-RNA causes a second separate effect that disrupts extracellular matrix mRNA regulation through a related CUG-RNA binding protein MBNL2. These findings reveal unanticipated similarities between DM1 and other muscular dystrophies, and open the way for approaches to treat DM1.