Overexpressing Key Protein Restores Heart Function in Muscular Dystrophy Model

Myotonic Dystrophy Type 1 (DM1) is the most common adult-onset form of muscular dystrophy and a condition that severely affects multiple organs including skeletal muscle, heart, brain and the gastrointestinal tract.

Cardiac problems affect 50% of individuals with DM1 and are the second leading cause of mortality, after respiratory insufficiency resulting from skeletal muscle wasting. In this study, researchers at Baylor College of Medicine and their collaborators focused on the DM1 heart problems testing a novel approach to restore normal function. The study appeared in The Journal of Clinical Investigation.

“DM1 is caused by a mutation in the DMPK gene that adds a repeating triplet of DNA building blocks (CTG) into the gene. While the unaffected population carries 5 to 37 CTG repeats, people with the condition have 50 to more than 3,000 repeats,” explained corresponding author Dr. Thomas A. Cooper,  professor of pathology and immunology, of molecular and cellular biology and of molecular physiology and biophysics at Baylor.

The mutant DMPK gene produces an RNA containing a copy of the repeated building blocks that sequesters a family of RNA-binding proteins called muscleblind-like (MBNL). Captured by this mutated DMPK RNA, MBNL proteins cannot carry out their function, which disrupts the RNA processing of hundreds of other genes, leading to the condition.

“Loss of MBNL function is thought to be the main cause of DM1. In this study, we tested the possibility that adding back MBNL protein in the heart would reverse the problems associated with the condition, such as electrical conduction delays and arrhythmias,” said first author Rong-Chi Hu, graduate student in the Cooper lab.

The team tested this approach in a mouse model they had developed that replicates many of the cardiac characteristics observed in the human disease.

"Overexpressing MBNL led to the restoration of some heart functions and characteristics, including conduction delays, pumping dysfunction and an enlarged heart, as well as disruptions in RNA processing,” Hu said, “but we were surprised that we couldn’t achieve more than about 50% rescue.”

“We explored the possibility that not enough MBNL was expressed in the heart to restore normal function but found that expressing 4 or 10 times as much MBNL as normal mice did not rescue heart functions further,” said Cooper, who also is the S. Donald Greenberg and R. Clarence and Irene H. Fulbright Professor and a member of the Dan L Duncan Comprehensive Cancer Center at Baylor.

“The findings are relevant to current therapeutic approaches for DM1 that are based on increasing MBNL. DM1 is a complex condition that involves disruption of the normal expression of hundreds of genes in the body.

"The next step is to understand why adding MBNL didn’t show more rescue and identify what other processes might be disrupted by the repeat RNA,” Cooper said.

Reference: Hu RC, Zhang Y, Nitschke L, et al. MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model. J Clin Invest. 2025. doi: 10.1172/JCI186416

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