Language
English
Publication Date
2-11-2025
Journal
Journal of Clinical Investigation
DOI
10.1172/JCI186416
PMID
39932794
PMCID
PMC11957708
PubMedCentral® Posted Date
2-11-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explored MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile dysfunction, hypertrophy, and misregulated alternative splicing and gene expression. While robust, the rescue was partial compared with reduced CUGexp RNA and plateaued with increased exogenous MBNL expression. These findings demonstrate that MBNL loss is a major contributor to DM1 cardiac manifestations and suggest that additional mechanisms play a role, highlighting the complex nature of DM1 pathogenesis.
Keywords
Animals, Myotonic Dystrophy, RNA-Binding Protein, Arrhythmias, Cardiovascular disease, Genetic diseasess, Mice, Disease Models, Animal, Mice, Transgenic, Myotonin-Protein Kinase, Alternative Splicing, Phenotype, Humans, Myocardium, DNA-Binding Proteins, Genetics, Therapeutics
Published Open-Access
yes
Recommended Citation
Hu, Rong-Chi; Zhang, Yi; Nitschke, Larissa; et al., "Mbnl Overexpression Rescues Cardiac Phenotypes in a Myotonic Dystrophy Type 1 Heart Mouse Model" (2025). Faculty and Staff Publications. 3982.
https://digitalcommons.library.tmc.edu/baylor_docs/3982