Severe skeletal muscle wasting is the most debilitating symptom experienced by individuals with myotonic dystrophy type 1 (DM1). We present a DM1 mouse model with inducible and skeletal muscle-specific expression of large tracts of CTG repeats in the context of DMPK exon 15. These mice recapitulate many findings associated with DM1 skeletal muscle, such as CUG RNA foci with Muscleblind-like 1 (MBNL1) protein colocalization, misregulation of developmentally regulated alternative splicing events, myotonia, characteristic histological abnormalities, and increased CUGBP1 protein levels. Importantly, this DM1 mouse model recapitulates severe muscle wasting, which has not been reported in models in which depletion of MBNL1 is the main feature. Using these mice, we discovered previously undescribed alternative splicing events that are responsive to CUGBP1 and not MBNL, and these events were found to be misregulated in individuals with DM1. Our results indicate that increased CUGBP1 protein levels are associated with DMPK-CUG RNA expression, suggesting a role for CUGBP1-specific splicing or cytoplasmic functions in muscle wasting.alternative splicing ͉ CUG-binding protein 1 ͉ Muscleblind-like 1 ͉ muscle atrophy ͉ microsatellite expansion M yotonic dystrophy type 1 (DM1) is a multisystemic, autosomal dominant disease caused by a CTG repeat expansion in the 3Ј untranslated region (UTR) of the DMPK gene (exon 15). Individuals with the disease have expansions ranging from 50 to Ͼ2,000 repeats. Onset and severity of disease correlate with repeat expansion size. The dominant organ system affected is skeletal muscle, which exhibits myotonia and degeneration. Severe skeletal muscle wasting is the primary cause of morbidity and mortality (1).After transcription of the expanded allele, CUG repeats accumulate within the nucleus in discrete RNA foci. Pathology in DM1 is a result of toxic RNA expression and not alteration of DMPK gene expression. This model was solidified by work from Mankodi et al. (2) using HSA LR transgenic mice that expressed 250 CUG repeats in the human skeletal actin 3Ј UTR specifically in skeletal muscle. HSA LR mice develop DM1-characteristic RNA foci, misregulated alternative splicing, myotonia, and histological abnormalities (2). Additionally, a second form of DM (DM2) is caused by expanded CCTG repeats in intron 1 of an unrelated gene, ZNF9, and yet has similar symptoms to those seen in DM1 (3, 4). Accumulation of toxic CUG or CCUG repeats leads to a transdominant misregulation of RNA homeostasis. In particular, developmentally regulated alternative splicing is affected such that there is a failure to express adult isoforms. Thus, pathology results at least in part from inappropriate expression of embryonic splicing patterns in adult tissues (5).Two proteins identified as interacting with CUG RNA repeats, Muscleblind-like 1 (MBNL1) and CUG-binding protein 1 (CUGBP1), play important roles in DM1 pathogenesis. Both proteins normally regulate alternative splicing of exons that are misregulated in DM1 (7, 24)...
