Myotonic dystrophy type 1 (DM1) is the most common cause of adult-onset muscular dystrophy. Muscular dystrophy is a genetic disease that causes muscle weakness and wasting, but also affects the brain, gastrointestinal tract, and heart. In a study published in Journal of Clinical Research Insights, Researchers at Baylor College of Medicine focused on the effects of DM1 on the heart. Their findings help answer questions about why the disease worsens over time and whether the damage once set can be reversed.
Cardiac symptoms affect most DM1 patients. Heart problems are primarily electrical conduction abnormalities, found in up to 75% of adult DM1 cases, which can lead to life-threatening arrhythmias that account for 25% of mortality and are the second leading cause of death in DM1. ”
Dr. Thomas A. Cooper, Corresponding author, Professor of Pathology and Immunology, Molecular Cell Biology, and Integrative Physiology at Baylor University
“DM1 is DMPK Genes that add repeating triplets of DNA building blocks (CTGs) to genes. “Unaffected populations have between 5 and 37 CTG repeats, while people with the disease have between 50 and more than 4,000 repeats,” explained Rong-Chi Hu, Ph.D., a postdoctoral fellow in Cooper’s lab and first author.
this DMPK The mutation causes the production of a defective RNA molecule that captures a protein called muscle blind-like (MBNL). Loss of MBNL function is thought to be the main cause of DM1. MBNL proteins normally help process RNA during development, including controlling how genes are spliced (cleaved and joined), which is necessary for normal gene function. When the MBNL protein is captured, it is unable to perform its function and some aspects of development are altered.
“The effects of the disease are known to worsen over time in all affected tissues,” Professor Cooper said. “One of the reasons that has been proposed to explain the increase in disease severity over time is that CTG repeats expand and their number increases. A patient may be born with 300 repeats, but later in life some tissues will have thousands of repeats. As the number of repeats increases, they sequester more MBNL, making the RNA increasingly toxic.”
In the current study, Hu, Cooper and colleagues observed the progression of DM1 heart disease in an animal model with long-term expression of toxic RNA. This model tests for disease progression without CTG repeat expansion, as repeat number does not increase over time.
“We followed the progression of heart disease in these animals for up to 14 months and found that the mice developed heart enlargement and significant electrical abnormalities early on,” Hu said. “Over time, the heart weakened, developing life-threatening rhythms and fibrosis (scarring), and the heart chambers became elongated and enlarged. Mice exposed to the toxic RNA for long periods also had shorter lifespans compared to age-matched control mice, especially males.”
Interestingly, the molecular effects of a nonfunctional MBNL protein, particularly aberrant RNA splicing, appeared early but did not worsen over time. This finding suggests that the loss of MBNL function did not change over time and is consistent with a stable CTG repeat number in this model. “We conclude that heart disease progression in this animal model is not due to increased loss of MBNL function. This result supports further investigation of other potential contributing factors to disease progression,” Cooper said. “For example, long-term exposure to toxic RNA can cause cumulative damage to the heart, leading to structural remodeling, fibrosis, and decreased function.”
The researchers also investigated whether damage to the heart could be reversed. Will the heart recover if we stop the toxic RNA? Does timing matter?
“When we turned off the RNA after a short exposure, the size, electrical function and structure of the heart returned to almost normal,” Hu said. “This was encouraging. When we turned off the RNA after many months, the recovery was significant but incomplete. Although the aberrant RNA splicing was completely corrected, physical changes such as thickening of the heart wall, conduction slowing, and fibrotic scar tissue were often not completely reversed, especially in male mice. Fibrosis is a concern because it interferes with electrical signal transmission and predisposes us to fatal arrhythmias.”
This study also revealed clear sex differences that mirror those seen in DM1 patients. “Male mice generally developed more severe heart disease, exhibited more severe rhythm disturbances, and had slower recovery after turning off the repeat RNA,” Professor Hu said. “This highlights the need to better understand how biological sex influences heart disease risk and treatment response in DM1.”
“Taken together, these findings deepen our understanding of DM1 heart disease and show that long-term exposure to toxic RNA can worsen heart disease, even if the genetic mutation does not spread,” Professor Cooper said. “We also show that while early intervention can reverse many heart conditions, if treatment is delayed, damage accumulates and becomes difficult to reverse. This study also highlights the importance of early monitoring of cardiac symptoms and early treatment in DM1.”
Mohammadreza Tabary and Xander HT Wehrens from Baylor College of Medicine also contributed to the study.
This research was supported by the Muscular Dystrophy Association (grant #276796), the National Institutes of Health (grants R01HL147020, R01AR082852, R01HL153350, R01HL160992, R01HL174510, R01HL180477, S10OD032380, UM1HG006348 and R01DK114356), Myotonic Dystrophy Foundation Predoctoral Fellowship and American Heart Association Predoctoral Fellowship (23PRE1020500).
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Baylor College of Medicine
Reference magazines:
Hu, R.-C., Others. (2026). Progressive cardiac phenotype and non-reversible decline due to long-term CUGexp RNA expression in the DM1 mouse model. JCI Insights. DOI: 10.1172/jci.insight.204278. https://insight.jci.org/articles/view/204278
