Progressive cardiac phenotypes and reduced reversibility from long-term CUGexp RNA expression in a DM1 mouse model

Myotonic Dystrophy Type 1 (DM1) is caused by an expanded CTG repeat in the DMPK gene, resulting in mutant transcripts that form expanded CUG (CUG_exp) RNA foci and sequester muscleblind-like (MBNL) RNA-binding proteins. DM1 is multisystemic with progressive worsening of disease manifestations in affected tissues. Disease progression is attributed to somatic expansion of the CTG repeats with age, resulting in production of CUG_exp RNA with enhanced intrinsic toxicity due to increased MBNL sequestration. To determine the degree to which cardiac disease progression can occur independently of repeat expansion, we used a transgenic DM1 mouse model with inducible heart-specific expression of a stable, interrupted 960-CUG repeat RNA. Sustained CUG_exp RNA expression caused progressive cardiac enlargement, contractile dysfunction, conduction delay, myocardial fibrosis, and reduced survival, while MBNL-dependent splicing defects remained static, consistent with the stable repeat length. We also determined the degree of reversibility after different periods of CUG_exp RNA expression by shutting off the repeat-containing transgene. Suppression of CUG_exp RNA expression rescued cardiac abnormalities, but reversibility declined with longer exposure to the toxic RNA. These findings demonstrate that prolonged expression of stable CUG_exp RNA drives progressive cardiac pathology, revealing a mechanism of disease progression in DM1 in addition to somatic expansion.

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