Dialing back muscle stiffness may help protect and preserve muscle health in people with myotonic dystrophy

Rochester, New York – A new study is offering scientists a different way of thinking about myotonic dystrophy type 1 (DM1), suggesting that one of the disease’s most recognizable symptoms may be doing far more than signaling illness. Researchers now believe that muscle stiffness, long viewed primarily as an uncomfortable consequence of the disorder, may actively contribute to the muscle damage that develops over time.

The findings, published in Nature Communications, point to muscle stiffness—known medically as myotonia—as a possible driver of muscle weakness and wasting. If confirmed through additional research, the discovery could reshape future treatment strategies by encouraging therapies that target both the genetic cause of the disease and one of its most visible symptoms.

For many years, scientists studying DM1 have concentrated on understanding its genetic origins. The inherited disorder is caused by a mutation in the DMPK gene, but unlike many genetic diseases, the mutation does not produce a defective protein. Instead, it creates a toxic RNA molecule that interferes with the normal processing of genetic information inside cells.

That disruption affects hundreds or even thousands of genes, causing errors in a process known as RNA splicing. As a result, many proteins produced throughout the body are altered, contributing to a wide range of health problems experienced by people living with the disease.

DM1 is the most common form of adult muscular dystrophy. In addition to progressive muscle weakness and muscle loss, patients often experience delayed muscle relaxation after contraction, irregular heart rhythms, cataracts, excessive daytime sleepiness and numerous other complications that can worsen over time.

Although researchers have understood for decades that toxic RNA lies at the center of the disease, determining exactly which of the many resulting biological changes are responsible for muscle deterioration has proven far more difficult.

The new research from the University of Rochester Medical Center focused on one particular consequence of the disease: myotonia. This condition occurs when muscles have difficulty relaxing after they contract, leading to prolonged stiffness that can interfere with everyday movement.

Scientists have known that myotonia develops because the disease disrupts a gene responsible for producing an important chloride channel. Under normal conditions, the channel helps muscles return to a relaxed state after contraction. When the channel does not function correctly, muscle cells become overly excitable, causing the delayed relaxation characteristic of DM1.

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Until now, however, many researchers considered myotonia largely a symptom rather than an active contributor to disease progression.

The new study challenges that assumption.

“Our findings suggest that myotonia isn’t simply an uncomfortable symptom people experience,” said John Lueck, PhD, associate professor of Pharmacology and Physiology at University of Rochester Medicine and senior author of the study. “It appears to amplify the harmful effects of the disease in muscles. When we eliminated myotonia in our mouse model, we didn’t just improve muscle relaxation; we saw healthier muscles overall.”

That observation led researchers to ask an important question. If the underlying toxic RNA remains present, could reducing muscle stiffness alone still improve muscle health?

Rather than attempting to eliminate the toxic RNA itself, the research team chose a different strategy. They genetically corrected one critical section of the chloride channel gene in a mouse model of DM1. This approach was designed specifically to prevent myotonia while leaving the original disease-causing mutation untouched.

The scientists expected the intervention to reduce muscle stiffness.

Instead, they observed improvements extending well beyond muscle relaxation.

Mice that no longer developed myotonia also produced stronger muscle contractions, displayed healthier muscle tissue under microscopic examination and showed broad improvements in abnormal gene expression and RNA splicing.

Those findings suggest that muscle stiffness may influence the severity of the disease much more than previously appreciated.

Lueck compared myotonia to a control that increases the disease’s overall impact.

“The toxic RNA is still present,” he said. “But myotonia appears to turn up the damage happening in muscles. When we turned myotonia down, many aspects of muscle health improved, even though we hadn’t corrected the original genetic mutation.”

The idea emerged from earlier research conducted by the same team.

Previous studies had shown that when myotonia occurred alongside another genetic splicing defect involving calcium channels, muscle disease became substantially more severe in laboratory mice. Researchers also found that treating those animals with calcium channel-blocking medications reversed many of the damaging effects.

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Those earlier results hinted that muscle hyperactivity itself might contribute directly to degeneration rather than simply reflecting damage already caused by the disease.

The new study allowed scientists to isolate that possibility more clearly.

“We’ve spent years trying to understand which of the many splicing changes actually matter most,” Lueck said. “This study allowed us to isolate one of those changes and ask what happens when you permanently remove myotonia while leaving the underlying disease process in place.”

The findings arrive as several experimental therapies aimed at treating DM1 continue advancing through development. Most of those treatments focus on removing or neutralizing the toxic RNA molecule responsible for disrupting RNA splicing throughout the body.

Researchers have often relied on improvements in myotonia as one of the earliest signs that these emerging treatments are working because the chloride channel tends to respond relatively quickly when genetic corrections begin taking effect.

The latest results suggest those improvements may represent more than a useful measurement.

Reducing muscle stiffness itself may help preserve muscle tissue and improve muscle performance, even before the underlying genetic abnormality is fully corrected.

That possibility could broaden treatment strategies in the future.

Instead of viewing therapies aimed at reducing myotonia simply as ways to improve comfort, physicians may eventually consider them important tools for slowing disease progression alongside RNA-based treatments.

The study also shines new light on medications that already exist.

Drugs including mexiletine and ranolazine are capable of reducing myotonia and improving muscle relaxation in some patients. However, their long-term use has often been limited because of side effects, and many individuals living with DM1 never receive them.

The new findings suggest these medications—or improved versions developed in the future—could play a larger role in disease management if researchers are able to create treatments that are both safer and easier for patients to tolerate.

“If we can develop safer, better-tolerated myotonia drugs, they could become an important complement to RNA-based therapies—or provide meaningful benefit for patients who don’t have access to those advanced treatments,” said Lueck.

Although the research was conducted in mice, the study provides scientists with valuable insight into how different biological processes interact during DM1 progression. Rather than focusing exclusively on the disease’s genetic origin, the work highlights how secondary changes may significantly influence long-term muscle health.

It also underscores the complexity of myotonic dystrophy, where a single inherited mutation triggers widespread effects throughout the body. Understanding which of those downstream changes cause the greatest harm could help researchers prioritize future therapies that deliver the greatest benefit for patients.

The research builds on decades of work investigating DM1 biology, including important contributions from University of Rochester Medicine neurologist Charles Thornton, MD, a co-author of the study. Previous research helped establish how toxic RNA disrupts RNA splicing, laying the foundation for today’s experimental genetic therapies.

Joining Lueck and Thornton on the study were Matthew T. Sipple, Sakura A. Hamazaki, Lily A. Cisco, Christina S. Heil and Katherine M. Lupia from the University of Rochester Medical Center, Vanessa Todorow of Yale University, and Peter Meinke of the Friedrich-Baur-Institute in Germany.

Funding for the research was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Myotonic Dystrophy Foundation, the National Institute of Dental and Craniofacial Research, the National Institute of General Medical Sciences and the German Research Foundation.

While additional studies will be needed before the findings can be translated into patient care, the work offers a fresh perspective on a disease that has challenged scientists for decades. By showing that reducing muscle stiffness may also reduce muscle damage, the study opens a promising avenue that could complement future genetic therapies and ultimately improve outcomes for people living with myotonic dystrophy type 1.