MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model
Rong-Chi Hu, … , Zheng Xia, Thomas A. Cooper
Rong-Chi Hu, … , Zheng Xia, Thomas A. Cooper
Published February 11, 2025
Citation Information: J Clin Invest. 2025;135(7):e186416. https://doi.org/10.1172/JCI186416.
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MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model

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.

Authors

Rong-Chi Hu, Yi Zhang, Larissa Nitschke, Sara J. Johnson, Ayrea E. Hurley, William R. Lagor, Zheng Xia, Thomas A. Cooper

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Figure 5

MBNL overexpression partially rescues disrupted ventricular splicing events related to cardiac morphology and function.

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MBNL overexpression partially rescues disrupted ventricular splicing eve...
(A) Alternative splicing signature scores for ventricle samples. The center line indicates the median value, while the upper and lower dashed lines indicate the first and third quartiles. (B) Number and types of alternative splicing events observed in ventricles. IR, intron retention. (C) Percentage of overlapping CE splicing events in each MBNL-overexpressing cohort using the comparison between CUG960 +/–dox and +dox cohorts as a reference. (D) Genes showing differential alternative splicing changes in comparisons of CUG960 –dox mice with +dox mice, as well as in comparisons of all MBNL cohorts to CUG960 +dox cohort were evaluated for enrichment of GO functional terms using the ShinyGO platform. The dashed vertical line: –log10(FDR) = 1.5 (E) Representative polyacrylamide gels showing alternative splicing changes for the candidate genes Scn5A, Tnnt2, and Ryr2 in ventricles of CUG960 +dox mice that underwent different treatments. (F) Quantification of the PSI for each splicing event. n = 3 animals per cohort. Black lines represent the significant differences in the corresponding groups compared with +dox or tdTomato controls; brown lines represent the significant differences between the corresponding groups and +/–dox and –dox controls. E, exon. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA with Tukey’s multiple-comparison test.