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, gastrointestinal tract and heart. In a study published in Journal of Clinical Investigation Insight, 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 can be reversed once it starts.
Cardiac manifestations affect most patients with T1DM. Cardiac problems are mainly electrical conduction abnormalities, seen in up to 75% of adult T1D cases, which can lead to life-threatening arrhythmias that account for 25% of mortality and are the second leading cause of death in T1D.”
Dr. Thomas A. Cooper, the corresponding author, professor of pathology and immunology, molecular and cellular biology, and integrative physiology at Baylor
“DM1 arises due to a mutation in DMPK gene that adds a repeating triplet of DNA structural units (CTG) to 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 The mutation leads to the production of defective RNA molecules that trap proteins called muscle blinds (MBNL). Loss of MBNL function is thought to be the primary cause of DM1. MBNL proteins normally help process RNA during development, including controlling how genes are spliced (cut and joined), which is required for normal gene function. When MBNL proteins get trapped, they can’t do their job, changing certain aspects of development.
“The effect of the disease is known to worsen over time in all affected tissues,” Cooper said. “One of the reasons proposed to explain the increased severity of the disease over time is that the CTG repeats expand, there are more of them – a patient may 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 more toxic because it binds more MBNL.”
In the current study, Hu, Cooper and colleagues followed 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 disease progression is controlled 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 an enlarged heart and significant electrical abnormalities,” Hu said. “As time went on, their hearts weakened, developed life-threatening rhythms and fibrosis (scarring), and the heart chambers stretched and enlarged.
Interestingly, the molecular consequences of having non-functional MBNL proteins – especially 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 the constant number of CTG repeats in this model. “We conclude that heart disease progression in this animal model is not driven by increasing loss of MBNL function. The results support further exploration of other potential contributors to disease progression,” Cooper said. “For example, prolonged exposure to toxic RNA could cause cumulative damage to the heart, leading to structural remodeling, fibrosis and reduced function.”
The researchers also investigated whether the damage to the heart could be reversed. Would disabling the toxic RNA allow the heart to recover? Does time matter?
“When we disabled the RNA after a short exposure, the heart’s size, electrical function and structure largely returned to normal,” Hu said. “This was encouraging. When the RNA was turned off after many months, the recovery was significant but incomplete. Although abnormal RNA splicing was completely corrected, physical changes such as thickened heart walls, conduction delays, and fibrous scar tissue were often not completely reversed, particularly in male mice.
The study also revealed clear gender differences, mirroring what is seen in people with T1DM. “Male mice generally developed more severe heart disease, had worse rhythm disturbances and had less recovery after knocking out the repetitive RNA,” Hu said. “This highlights the need to better understand how biological sex affects heart disease risk and treatment response in T1DM.”
“Together, these findings improve our understanding of heart disease in T1DM, showing that it can be exacerbated by prolonged exposure to toxic RNA, even if the genetic mutation does not spread,” Cooper said. “They also show that while early intervention can reverse many heart problems, delayed treatment allows damage to accumulate and be more difficult to reverse. This study also highlights the importance of early monitoring and early treatment of cardiac symptoms in T1DM.”
Mohammadreza Tabary and Xander HT Wehrens, both at Baylor College of Medicine, also contributed to this work.
This study was funded by the Muscular Dystrophy Association (grant #276796), National Institutes of Health (grants R01HL147020, R01AR082852, R01HL153350, R01HL160992, R01HL174510, R0470201, R01HL14702, UM1HG006348, and R01DK114356), a Myotonic Dystrophy Foundation predoctoral fellowship, and an American Heart Association predoctoral fellowship (23PRE1020500).
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