For decades, researchers studying myotonic dystrophy type 1 (DM1) have focused on the disease's underlying genetic cause: a mutation that produces a toxic form of RNA, disrupting the normal processing of thousands of genetic messages inside cells. While scientists have known this widespread disruption contributes to disease, it has remained unclear which changes are most responsible for the progressive muscle weakness and wasting experienced by people living with DM1.
Now, a new study published in Nature Communications suggests that one hallmark symptom of the disease—muscle stiffness, known as myotonia—may play a much larger role in driving muscle damage than previously recognized.
"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."
The findings suggest that therapies aimed at reducing myotonia could help preserve muscle function while complementing emerging treatments designed to address the disease's underlying genetic cause.
A disease caused by toxic RNA
DM1 is the most common form of adult muscular dystrophy. The inherited disorder causes progressive muscle weakness, muscle wasting, slow relaxation after muscle contraction, heart rhythm abnormalities, cataracts, excessive daytime sleepiness, and a range of other symptoms.
The disease begins with an abnormal expansion of repeated DNA segments in the DMPK gene. Rather than producing a faulty protein, this mutation creates a toxic RNA molecule that traps proteins needed to correctly process genetic instructions. As a result, hundreds to thousands of genes are improperly "spliced," producing abnormal protein versions throughout the body. Decades of research led by URochester Medicine neurologist Charles Thornton, MD , a co-author of the study, helped establish how this toxic RNA disrupts normal RNA splicing and drives the disease.
One of the most important affected genes expresses a chloride channel that helps muscles relax after they contract. When that channel is disrupted, muscles become electrically overactive, producing the delayed relaxation known as myotonia.
Looking beyond the root cause
Most research has focused on eliminating the toxic RNA itself, with several RNA-targeted therapies now advancing toward clinical use. However, Lueck and his colleagues wanted to answer a different question: once myotonia develops, does it simply reflect the disease, or does it actively worsen muscle damage?
Previous work from the URochester Medicine team had hinted at the answer. They found that when myotonia occurred alongside another splicing defect affecting calcium channels, muscle disease became dramatically worse in mice. Treating those mice with calcium channel-blocking drugs reversed many of the effects. That finding suggested that muscle hyperexcitability might be directly contributing to muscle degeneration.
"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."
Turning down the disease's "volume"
To answer that question, the researchers genetically corrected a single critical portion of the chloride channel gene in a mouse model of DM1. The researchers expected to reduce muscle stiffness. Instead, they saw improvements throughout the muscle.
The mice no longer developed muscle stiffness, but they also generated greater muscle force, showed healthier muscle tissue under the microscope, and experienced broad improvements in abnormal gene expression and RNA splicing. The findings suggest myotonia may act as what Lueck describes as a "volume knob" on the disease.
"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."
Implications for future treatments
The findings could influence how researchers think about treating DM1. Several experimental therapies currently in development are designed to eliminate the toxic RNA that causes the disease. Researchers have long used improvements in myotonia as an early sign that these therapies are working because the chloride channel is particularly sensitive to correction.
The new study suggests that reducing myotonia may itself contribute significantly to improved muscle health. In other words, treating myotonia may do more than relieve stiffness—it may actually help slow or reduce the muscle damage caused by the disease.
At the same time, existing medications that reduce myotonia—including drugs such as mexiletine and ranolazine—may deserve renewed attention. Although these medications can improve muscle stiffness, side effects often limit their long-term use, and many people with DM1 never receive them.
"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.
Additional co-authors include Matthew T. Sipple, Sakura A. Hamazaki, Lily A. Cisco, Christina S. Heil, and Katherine M. Lupia with URochester Medicine, Vanessa Todorow with Yale University, and Peter Meinke with the Friedrich-Baur-Institute in Germany. The study was funded with support from 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.
