University of Rochester Medicine researchers found in a mouse model that the muscle stiffness associated with myotonic dystrophy type 1 may actively worsen muscle damage instead of serving only as a symptom.
The study, published in Nature Communications, suggests that treatments aimed at reducing stiffness could help preserve muscle function while complementing emerging therapies that target the disease's underlying genetic cause.
Myotonic dystrophy type 1, also known as DM1, is the most common form of adult muscular dystrophy. The inherited disorder can cause progressive muscle weakness and wasting, delayed relaxation after muscle contraction, heart rhythm problems, cataracts, excessive daytime sleepiness and other symptoms.
How stiffness may drive damage
DM1 begins with an abnormal expansion of repeated DNA segments in the DMPK gene. That mutation produces a toxic form of RNA that traps proteins needed to process genetic instructions correctly, causing hundreds or thousands of genes to be improperly spliced and creating abnormal proteins throughout the body.
One affected gene produces a chloride channel that helps muscles relax after they contract. Disruption of that channel makes muscles electrically overactive and causes myotonia, the delayed relaxation or stiffness associated with the disease.
Researchers have long focused on removing the toxic RNA. John Lueck, an associate professor of pharmacology and physiology at Rochester and senior author of the study, said the new work examined whether myotonia merely reflects the disease or contributes to worsening muscle health.
Correcting one gene segment brought broader gains
The team genetically corrected a critical portion of the chloride channel gene in a mouse model while leaving the underlying disease process in place. Researchers expected the change to reduce muscle stiffness, but they also found that the mice produced greater muscle force and had healthier muscle tissue.
The correction also led to broad improvements in abnormal gene activity and RNA splicing. Lueck described myotonia as acting like a volume control that amplifies damage in muscle even when the toxic RNA remains present.
The findings build on earlier Rochester research showing that myotonia combined with another splicing defect affecting calcium channels made muscle disease substantially worse in mice. In that work, calcium channel-blocking drugs reversed many of the effects.
Findings could shape treatment research
Several experimental therapies moving toward clinical use are designed to remove the toxic RNA that causes DM1. The new study indicates that reducing myotonia may itself improve muscle health, potentially adding benefit beyond relief from stiffness.
Existing drugs including mexiletine and ranolazine can reduce myotonia, but the researchers said side effects may limit long-term use and many people with DM1 do not receive them. Lueck said safer, better-tolerated medicines targeting myotonia could complement RNA-based treatment or help patients who cannot access advanced therapies.
The study's Rochester co-authors included Matthew T. Sipple, Sakura A. Hamazaki, Lily A. Cisco, Christina S. Heil, Katherine M. Lupia and neurologist Charles Thornton. Researchers from Yale University and the Friedrich-Baur-Institute in Germany also contributed.
Funding came from several federal research institutes, the Myotonic Dystrophy Foundation and the German Research Foundation.
FingerLakes1.com is the region’s leading all-digital news publication. The company was founded in 1998 and has been keeping residents informed for more than two decades. Have a lead? Send it to news@fingerlakes1.com.