Researchers at Baylor College of Medicine announced on Apr. 3 that long-term exposure to toxic RNA drives progressive heart damage in myotonic dystrophy type 1 (DM1), according to a study published in the Journal of Clinical Investigation Insight. The findings help explain why the disease gets worse over time and explore whether cardiac damage can be reversed once it has started.
Myotonic dystrophy type 1 is a genetic disorder that causes muscle weakness and wasting, but also affects other organs such as the brain, gastrointestinal tract, and heart. The research focused on how DM1 impacts the heart, which is critical for understanding patient outcomes and potential treatments.
"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.
The mutation results in faulty RNA molecules that trap proteins called muscleblind-like (MBNL), leading to abnormal gene splicing required for normal function. "It's known that the effect of the disease gets worse over time in all affected tissues," said Dr. Thomas A. Cooper from Baylor College of Medicine. He added that as CTG repeats increase, so does RNA toxicity due to more MBNL being sequestered.
In animal models where toxic RNA was expressed without increasing repeat numbers over time, researchers observed worsening heart problems including enlarged hearts, electrical abnormalities, life-threatening arrhythmias, fibrosis (scarring), and shortened lifespans—especially among male mice. "We followed the progression of heart disease in these animals for up to 14 months... As time went on, their hearts became weaker... Mice with long-term exposure... had shorter lives compared to age-matched control mice," Hu said.
Molecular changes such as abnormal splicing appeared early but did not worsen further during prolonged exposure when repeat numbers were stable. This suggests factors beyond MBNL loss contribute to ongoing cardiac deterioration: "The results support further exploration of other potential contributors... For instance, prolonged exposure could cause cumulative damage leading to structural remodeling," Cooper said.
Turning off toxic RNA after short exposures led hearts back toward normal function; after longer exposures recovery was significant but incomplete—especially among males—with persistent scarring and electrical conduction issues remaining even after correcting molecular defects: "Fibrosis is a concern because it disrupts electrical signaling and makes deadly arrhythmias more likely," Hu said.
Sex differences were clear: "Male mice generally developed more severe heart disease... showed worse rhythm disturbances and had less recovery after repeat RNA was turned off," Hu noted.
Cooper concluded: "Taken together, these findings improve our understanding... showing it can worsen because of prolonged exposure even if genetic mutation does not expand... Early intervention can reverse many problems; delayed treatment allows damage to accumulate." The study highlights importance of early monitoring and intervention for cardiac symptoms in DM1.
