Researchers at Baylor College of Medicine and other institutions have developed a mouse model that mirrors many gastrointestinal (GI) symptoms seen in adults with myotonic dystrophy type 1 (DM1), the most common adult-onset muscular dystrophy. DM1 affects about one in 8,000 people and is known for causing muscle weakness and stiffness, but it also impacts organs such as the brain, heart, and GI tract. Approximately 80% of individuals with DM1 experience significant GI issues, including swallowing difficulties, delayed stomach emptying, constipation, and even intestinal obstruction.
The new study published in the Proceedings of the National Academy of Sciences identifies a key mechanism behind these GI symptoms. "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," said Dr. Thomas A. Cooper, corresponding author and professor at Baylor.
This genetic change leads to faulty RNA molecules that trap proteins called muscleblind-like (MBNL). The loss of MBNL function disrupts normal RNA processing during development. Although this process is linked to muscle stiffness and weakness in DM1 patients, its effect on GI problems was previously unclear.
"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," explained Janel A.M. Peterson, first author and graduate student at Baylor. "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."
Their research showed that food moved slower through both small intestine and colon when MBNL proteins were missing from gut smooth muscles in mice. Despite no visible signs of inflammation or nerve damage under microscopic examination, they observed thicker smooth muscle layers and shorter small intestines—indications that muscles were persistently contracted.
Further experiments revealed direct evidence: "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." According to Peterson's findings, this is clear evidence that losing MBNL function specifically in smooth muscle alters GI movement—a major symptom for those with DM1.
These insights could impact treatment approaches for DM1-related GI symptoms. Currently available drugs aim to stimulate gut movement but often fail or yield inconsistent results for DM1 patients. "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 noted.
On a molecular level, researchers identified increased phosphorylation—a chemical tag involved in activating contraction—of myosin light chain (MLC20), which supports their conclusion about constant contraction state within affected gut muscles. They also found multiple genes related to muscle contraction were altered similarly between mouse models and human tissue samples from DM1 patients.
"DM1 is a complex disease, and GI symptoms have long been understudied," said Cooper. "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."
The research team included contributors from Baylor College of Medicine; Texas Children's Hospital; Oregon Health & Science University; Stanford University; as well as support from various NIH grants and foundations dedicated to neuromuscular disease research.
