Myotonic dystrophy type 1 (DM1) is the most common cause of adult-onset muscular dystrophy, a genetic disorder that leads to muscle weakness and wasting, but also affects the brain, the gastrointestinal tract and the heart. In a study published in the Journal of Clinical Investigation Insight , researchers at Baylor College of Medicine focused on the effects of DM1 in the heart. Their findings help answer questions about why the disease worsens over time and whether the damage can be reversed once it has begun.
"Cardiac manifestations affect most DM1 patients," said corresponding author Dr. Thomas A. Cooper , professor of pathology and immunology , of molecular and cellular biology and of integrative physiology at Baylor. "Cardiac problems are primarily electric conduction abnormalities, seen in up to 75% of adult DM1 cases, which can result in life-threatening arrhythmias accounting for 25% mortality and the second leading cause of death in DM1."
"DM1 arises because of a mutation in the DMPK gene that adds a repeating triplet of DNA building blocks (CTG) into the gene. The unaffected population carries 5 to 37 CTG repeats, but people with the condition have 50 to more than 4,000 repeats," explained first author Dr. Rong-Chi Hu , a postdoctoral fellow in the Cooper lab .
This DMPK mutation leads to the production of faulty RNA molecules that trap proteins called muscleblind-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 (cut and joined), required for normal gene function. When MBNL proteins are trapped, they can't do their job, altering some aspects of development.
"It's known that the effect of the disease gets worse over time in all the affected tissues," Cooper said. "One of the reasons proposed to explain increased disease severity over time is that the CTG repeats expand, there's more of them – a patient might be born with 300 repeats, but later in life there will be thousands of repeats in some tissues. As the number of repeats increases, the RNA becomes increasingly more toxic because it sequesters more MBNL."
In the current study, Hu, Cooper and their colleagues monitored the progression of DM1 heart problems in an animal model in which the toxic RNA was expressed long-term. In this model the number of repeats does not increase over time, so this tests disease progression without CTG repeat expansion.
"We followed the progression of heart disease in these animals for up to 14 months and found that, early on, the mice developed enlarged hearts and significant electrical abnormalities," Hu said. "As time went on, their hearts became weaker, they developed life-threatening rhythms and fibrosis (scarring), and the heart chambers stretched and dilated. Mice with long-term exposure to the toxic RNA also had shorter lives compared to age-matched control mice, especially males."
Interestingly, the molecular consequences of having non-functional MBNL proteins – specifically abnormal RNA splicing – appeared early but did not worsen over time. This finding suggests the loss of MBNL function did not change over time and is consistent with the stable number of CTG repeats in this model. "We concluded that the progression of heart disease in this animal model is not due to increasing loss of MBNL function. The results support further exploration of other potential contributors to disease progression," Cooper said. "For instance, prolonged exposure to the toxic RNA could cause cumulative damage to the heart, leading to structural remodeling, fibrosis and declining function."
The researchers also investigated whether the damage to the heart could be reversed. Would turning off the toxic RNA allow the heart to recover? Does the timing matter?
"When we turned off the RNA after a short exposure, heart size, electrical function and structure largely returned to normal," Hu said. "This was encouraging. When the RNA was turned off after many months, recovery was significant but incomplete. Although abnormal RNA splicing was fully corrected, physical changes such as thickened heart walls, conduction delays and fibrotic scar tissue often were not reversed completely, particularly in male mice. Fibrosis is a concern because it disrupts electrical signaling and makes deadly arrhythmias more likely."
The study also revealed clear sex differences, mirroring what is seen in people with DM1. "Male mice generally developed more severe heart disease, showed worse rhythm disturbances and had less recovery after the repeat RNA was turned off," 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 improve our understanding of heart disease in DM1, showing that it can worsen because of prolonged exposure to toxic RNA, even if the genetic mutation does not expand," Cooper said. "They also show that while early intervention can reverse many heart problems, delayed treatment allows damage to accumulate and become harder to undo. This study also underscores the importance of early monitoring and early treatment of cardiac symptoms in DM1."
Mohammadreza Tabary and Xander H. T. Wehrens, both at Baylor College of Medicine, also contributed to this work.
This study was funded by Muscular Dystrophy Association (grant #276796), National Institutes of Health (grants R01HL147020, R01AR082852, R01HL153350, R01HL160992, R01HL174510, R01HL180477, S10OD032380, UM1HG006348 and R01DK114356), a Myotonic Dystrophy Foundation predoctoral fellowship and an American Heart Association predoctoral fellowship (23PRE1020500).
