New Mouse Study Shows How Myotonic Dystrophy Causes Over-Contracted Gut Muscles and Severe Digestive Problems

Myotonic dystrophy type 1, commonly known as DM1, is the most frequent form of adult-onset muscular dystrophy, affecting roughly 1 in every 8,000 people worldwide. The condition is widely recognized for causing muscle weakness, stiffness, and delayed relaxation, but for many patients, the most disruptive symptoms are not in the arms or legs. Instead, they occur deep within the gastrointestinal (GI) tract, quietly but profoundly reducing quality of life.

Up to 80% of people with DM1 experience gastrointestinal complications, including difficulty swallowing, delayed stomach emptying, chronic constipation, abdominal pain, and, in severe cases, intestinal obstruction. Despite how common and debilitating these problems are, the biological reasons behind them have remained poorly understood. A new study from Baylor College of Medicine and collaborating institutions has now provided some of the clearest answers to date.

Published in the Proceedings of the National Academy of Sciences (PNAS), the research introduces the first mouse model specifically designed to replicate the gastrointestinal features of DM1. The findings reveal that the root problem may not be weak gut muscles, as long assumed, but rather gut muscles that are stuck in a state of constant contraction.

Understanding the Genetic Cause of DM1

DM1 is caused by a mutation in the DMPK gene, where a short DNA sequence—CTG—is abnormally repeated. In unaffected individuals, this sequence repeats between 5 and 37 times. In people with DM1, the number of repeats jumps dramatically, ranging from 50 to more than 3,000.

This expansion does not primarily damage the DMPK protein itself. Instead, it leads to the production of toxic RNA molecules that interfere with normal cellular processes. These faulty RNA strands trap a group of proteins called muscleblind-like proteins, or MBNL proteins, preventing them from doing their normal job.

MBNL proteins play a critical role in RNA splicing, a process that determines how genes are assembled into functional instructions for cells. When MBNL proteins are unavailable, many genes are incorrectly spliced, leading to widespread dysfunction. This mechanism has long been linked to the muscle stiffness and weakness seen in DM1, but its role in gastrointestinal symptoms had not been clearly demonstrated until now.

Building a Gut-Specific Mouse Model

To isolate the cause of GI problems, the researchers took a highly targeted approach. Rather than altering the entire body, they selectively removed MBNL proteins only from smooth muscle cells in the gut of mice.

Smooth muscle lines the digestive tract and is responsible for moving food forward through rhythmic contractions, a process known as peristalsis. By focusing exclusively on these cells, the researchers could determine whether loss of MBNL function in smooth muscle alone was enough to reproduce the GI symptoms seen in DM1 patients.

The results were striking.

Slower Digestion Without Obvious Damage

Mice lacking MBNL proteins in their gut smooth muscle showed significantly slower movement of food through both the small intestine and the colon. This delayed transit closely mirrors what many people with DM1 experience in daily life.

What surprised the researchers was what they did not find. Under microscopic examination, the gut tissue appeared largely normal. There were no clear signs of inflammation, no nerve degeneration, and no obvious structural damage that would typically explain severe digestive dysfunction.

Instead, the smooth muscle layers of the intestine were thicker than normal, and the small intestine itself was shorter. These structural changes pointed toward a different explanation: the muscles were likely contracting too much, too often, and for too long.

Direct Evidence of Over-Contracted Gut Muscles

To test this idea, the researchers examined intestinal segments outside the body. These experiments revealed that the gut muscles were abnormally tense even at rest, contracted more forcefully than normal, and failed to relax properly after stimulation.

This provided the first direct evidence that loss of MBNL proteins in smooth muscle leads to gut muscle over-contraction, not weakness. In other words, the digestive system in DM1 may be struggling not because it cannot move food, but because it cannot relax enough to do so efficiently.

The Molecular Link to Constant Contraction

At the molecular level, the team focused on a protein called myosin light chain 20 (MLC20), which plays a central role in muscle contraction. When MLC20 is chemically modified through phosphorylation, muscle fibers contract.

In the DM1 mouse model, levels of phosphorylated MLC20 were significantly higher, supporting the idea that the gut muscles were locked in a hyper-contracted state. Further analysis showed that many other genes involved in regulating muscle contraction were also disrupted.

Importantly, these genetic changes were not unique to mice. The same patterns were observed in human DM1 tissue samples, confirming that the mouse model accurately reflects the human disease and is a reliable tool for future research.

Why Current Treatments Often Fall Short

Most current treatments for gastrointestinal symptoms in DM1 are designed to stimulate gut movement, based on the assumption that the digestive tract is sluggish or weak. These medications often produce inconsistent or disappointing results, and some patients experience little relief.

The new findings suggest that this approach may be fundamentally flawed. If the gut muscles are already overactive and overly contracted, stimulating them further could worsen the problem.

Instead, the research points toward a different strategy: reducing excessive muscle contraction. This aligns with recent clinical case reports in which antispasmodic medications—drugs that relax smooth muscle—have helped relieve severe GI symptoms in some DM1 patients.

Why Gastrointestinal Symptoms Matter in DM1

Gastrointestinal issues are often overshadowed by the more visible muscle symptoms of DM1, but they can be just as disabling. Chronic constipation, bloating, swallowing difficulties, and abdominal pain can interfere with nutrition, medication absorption, and overall well-being.

By clearly identifying smooth muscle over-contraction as a key mechanism, this study helps shift how clinicians and researchers think about digestive problems in DM1. It also opens the door to more targeted therapies that address the underlying biology rather than just the symptoms.

Extra Context: Smooth Muscle and Digestive Health

Smooth muscle is different from skeletal muscle. It works automatically, without conscious control, and is finely regulated by a balance of signals that promote contraction and relaxation. Even small disruptions in this balance can have large effects on digestion.

Conditions involving smooth muscle dysfunction are not unique to DM1. Similar mechanisms are studied in disorders like irritable bowel syndrome, achalasia, and certain forms of chronic constipation. Insights from this DM1 model could therefore have implications beyond a single disease.

A Step Forward for Patients and Research

By creating a GI-specific mouse model and carefully comparing it with human tissue, the researchers have filled a long-standing gap in DM1 research. The work highlights the importance of looking beyond muscle weakness and considering muscle regulation, especially in organs that rely on precise rhythmic movement.

For people living with DM1, this research offers something especially valuable: clarity. Understanding why symptoms occur is the first step toward treating them effectively, and this study provides a strong foundation for developing therapies that could meaningfully improve daily life.

Research paper:
https://www.pnas.org/doi/10.1073/pnas.2522788122