Researchers have discovered the specific biological mechanism that causes muscle dysfunction in myotonic dystrophy type 1 (DM1), a common form of muscular dystrophy. They also found that calcium channel blockers, a type of medication used for various heart conditions, can reverse these symptoms in animal models of the disease. This suggests that calcium channel blockers could be a potential treatment for DM1.
“Our study shows that a combination of calcium and chloride channel defects is very harmful and plays a key role in the muscle impairment of the disease,” said John Lueck, Ph.D., an assistant professor at the University of Rochester Medical Center (URMC) in the Departments of Pharmacology and Physiology, and Neurology.
“We also found that common calcium channel blockers can reduce muscle impairment in DM1 and that modulating calcium channels is a possible therapeutic strategy.” Lueck is the lead author of the study, which appears in the Journal of Clinical Investigation.
How toxic RNA affects muscle function
Myotonic dystrophy is one of the most common forms of muscular dystrophy. People with the disease have muscle weakness and prolonged muscle contraction (myotonia), which makes it hard to relax muscles after use. The disease also affects the eyes, heart, and brain, leading to problems with walking, swallowing, and breathing.
More than 20 years ago, URMC neurologist Charles Thornton, MD, and others revealed how a genetic mutation–a repeated sequence of code on a part of chromosome 19–causes DM1. This mutation, which gets longer over time, produces abnormal RNA that builds up in the cell nucleus and interferes with the normal processing of many other RNAs. Thornton is a co-author of the current study and the research was a collaboration between the Lueck and Thornton labs.
This abnormal RNA specifically disrupts the function of muscleblind-like (MBNL) proteins, which regulate the splicing of transcripts that are important for healthy muscle function. These splicing defects affect the function of receptors for calcium and chloride channels, which are pathways in muscle cells that help convert electrical signals from motor neurons into chemical signals within the muscle cells. The release of stored calcium makes muscle cells contract, a process called excitation-contraction coupling (ECC) while lowering the chemical concentration makes the cell relax.
How calcium channel blockers can help
Lueck and his colleagues wanted to understand this cycle better, as it could explain the muscle dysfunction in DM1. The first challenge was to isolate the muscle effect of the disease and remove the “noise” of the many other defects caused by the abnormal RNA. “Myotonic dystrophy is a very complex disorder, which you can think of as a collection of many diseases,” said Lueck. To do this, the team created a mouse model that copied four of the splicing defects found in DM1 in genes related to the calcium and chloride channels. These mice had severe myotonia, muscle weakness, reduced mobility, breathing problems, and a shorter lifespan.
The involvement of the calcium channel in muscle dysfunction presented an opportunity and a target—calcium channel blockers are widely used to treat, among other things, high blood pressure, cardiac arrhythmias, and migraines. When the team treated the mice with verapamil, a calcium channel blocker used to treat hypertension and chest pains, the mice quickly recovered muscle function and began to resemble their healthy, wild-type peers. The findings were possible by years of close observation of the animals by Lily Cisco, a graduate student in the Lueck lab who is the first author of the study.
The researchers are quick to emphasize that verapamil is not an appropriate treatment for DM1 in humans due to its potential cardiac side effects. “We think that the calcium channel is a new therapeutic target and if we can target it correctly, pharmacologically it will improve muscle function and health. Our goal now is to find the appropriate and safe calcium channel blocker that will do the job and we believe it exists.”