Language
English
Publication Date
5-8-2026
Journal
JCI Insight
DOI
10.1172/jci.insight.204278
PMID
41855125
PMCID
PMC13232024
PubMedCentral® Posted Date
3-19-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Myotonic dystrophy type 1 (DM1) is caused by an expanded CTG repeat in the DMPK gene, resulting in mutant transcripts that form expanded CUG (CUGexp) 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 CUGexp 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 CUGexp 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 CUGexp RNA expression by shutting off the repeat-containing transgene. Suppression of CUGexp RNA expression rescued cardiac abnormalities, but reversibility declined with longer exposure to the toxic RNA. These findings demonstrate that prolonged expression of stable CUGexp RNA drives progressive cardiac pathology, revealing a mechanism of disease progression in DM1 in addition to somatic expansion.
Keywords
Animals, Myotonic Dystrophy, Mice, Disease Models, Animal, Mice, Transgenic, Myotonin-Protein Kinase, Disease Progression, Trinucleotide Repeat Expansion, RNA-Binding Proteins, Phenotype, Myocardium, Cardiovascular disease, Genetic diseases, Molecular biology, Cardiology, Genetics
Published Open-Access
yes
Recommended Citation
Hu, Rong-Chi; Tabary, Mohammadreza; Wehrens, Xander Ht; et al., "Progressive Cardiac Phenotypes and Reduced Reversibility From Long-Term CUGexp RNA Expression in a DM1 Mouse Model" (2026). Faculty, Staff and Students Publications. 7453.
https://digitalcommons.library.tmc.edu/baylor_docs/7453