Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy, affecting about 1 in 8,000 people. While it is well known for causing muscle weakness and stiffness, DM1 also affects other organs, including the brain, heart and gastrointestinal (GI) tract. Although around 80% of people with DM1 experience GI problems that greatly reduce their quality of life, including difficulty swallowing, delayed stomach emptying, constipation and severe conditions like intestinal obstruction, the underlying causes remain understudied.
To shed light onto the causes and potential solutions to the GI problems associated with DM1, researchers at Baylor College of Medicine and collaborating institutions developed the first mouse model that replicates many of the GI problems observed in adults with the condition. The findings in mice and their comparison to human tissue uncovered a key mechanism and opened the door to potential new treatments that could significantly improve the lives of thousands of people living with this devastating condition. The study appeared in the Proceedings of the National Academy of Sciences .
"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.
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. These proteins normally help process RNA during development, including controlling how genes are spliced (cut and joined). When MBNL proteins are trapped, they can't do their job. This process is known to cause muscle stiffness and weakness, but its role in GI problems was unknown.
"To investigate how loss of MBNL proteins affects smooth muscle in the GI, we removed these proteins only from smooth muscle cells in the gut of mice," said first author Janel A.M. Peterson , graduate student in the Cooper lab . "Smooth muscle lines the intestines and moves food along. We focused on these cells to determine whether MBNL loss alone was enough to cause GI issues similar to those in DM1 patients."
The findings provided a novel, sometimes surprising view of how DM1 affects the GI. "We found that food moved slower through both the small intestine and colon of mice lacking MBNL proteins in their gut smooth muscle," Peterson said. "Unexpectedly, the gut tissue looked normal under the microscope – no signs of inflammation or nerve damage. However, the smooth muscle layers were thicker and the small intestine was shorter. These changes suggest the muscles were constantly contracting."
The team also found direct evidence of smooth muscle over-contraction. "When we tested gut segments outside the body, we found that the muscles were more "tense," contracted strongly at baseline and stayed tight after stimulation." This study provides the first clear evidence that MBNL loss in smooth muscle alone can alter GI movements, a major symptom in DM1.
The finding that GI smooth muscles in DM1 are over-contracted has implications for therapeutic interventions. Current treatments for GI symptoms in DM1 include drugs that stimulate gut movement. These treatments often fail or produce mixed results. "Our findings suggest that drugs that reduce gut muscle contraction, rather than stimulate it, might be more effective for DM1 patients. This aligns with recent case reports where antispasmodic drugs helped relieve severe symptoms," Cooper said.
Digging deeper into the molecular mechanisms of their observations, the researchers investigated the protein myosin light chain (MLC20), which is essential for muscle contraction. "When a phosphate chemical tag is added to MLC20, muscles contract," Peterson said. "We found higher levels of phosphorylated MLC20 in the DM1 gut model, which supports that their gut muscles are in a constantly contracted state."
The team also discovered that many other genes involved in controlling muscle contraction – not only MLC20 – were affected in their DM1 gut model. Importantly, many of these affected genes were shared between mice and humans, meaning the mouse model is a valuable tool to study the human condition.
"DM1 is a complex disease, and GI symptoms have long been understudied," Cooper said. "By creating a GI-specific mouse model and comparing it to human tissue, this study not only uncovered a key mechanism but points at new ways to develop treatments that could make a difference in people living with DM1."
Other contributors to this work include Jesus A. Frias, Andrew N. Miller, Krishnakant G. Soni, Yi Zhang, Zheng Xia, John W Day and Geoffrey A. Preidis. The authors are affiliated with Baylor College of Medicine, Texas Children's Hospital, Oregon Health & Science University and/or Stanford University.
This work was supported in part by NIH grants 1F31DK132935, R01AR082852, R01HL147020, R01DK133301 and R01GM147365, S10OD032380, UM1HG006348, R01DK114356, 1S10OD023469 and P30CA125123. Further support was provided by the National Cancer Institute and Cancer Prevention and Research Institute of Texas (CPRIT) (grant RP200504) and the National Institute of Diabetes and Digestive and Kidney Diseases (grant P30DK056338). The Stanford Neuromuscular Repository has been supported by the Myotonic Dystrophy Foundation, Marigold Foundation and Jack and Ben Kelly Fund.
