Adding exercise to genetic treatment reverses fatigue in mice with common myotonic dystrophy

Adding exercise to a genetic treatment for myotonic dystrophy type 1 (DM1) was more effective in reversing fatigue than administering the treatment alone in a study using a mouse model of the disease. In fact, exercise alone provided some benefit while genetic treatment alone did not. This study, led by Massachusetts General Hospital (MGH) researchers and collaborators, has implications for patients suffering from fatigue due to genetically-related musculoskeletal diseases and other types of disease-induced fatigue. The study appears in Molecular therapy – Nucleic acids.

It is encouraging that exercise makes a noticeable difference on its own and in combination with a specific genetic treatment for the disease. “

Thurman M. Wheeler, MD, Investigator, Department of Neurology at MGH and at Harvard Medical School

Wheeler was the senior author of the study.

DM1 is the most common muscular dystrophy in adults and one of several genetic conditions that cause muscle atrophy and progressive weakness. Patients with DM1 report that chronic fatigue is the most debilitating symptom of their condition, although the biological support for this effect is unknown. Wheeler and his colleagues wanted to test the value of exercise to reverse this symptom.

The disease is caused by a gain-of-function mutation that leads to the expression of higher levels of a genetic element called expanded microsatellite CUG repeat. The researchers used genetically modified mice to carry the same defect, and treated some of them with an antisense oligonucleotide, which is essentially a strand of genetic material that attaches to RNA to repair specific genetic defects.

Then they studied the effects of exercise on elderly mice with the genetic defect that received only the oligonucleotide, some that were only forced to exercise, others that had both treatment and exercise, and one group that received a placebo (a saline solution). They compared the post-exercise activity levels of the mice in each of those study arms. They also measured the responses of the young mice with the defect that just received the placebo. The activity of the mice was measured using a special type of fence that records the movement of the mouse.

This study provides preliminary answers to at least two questions: How much should scientists expect the efficacy of gene therapy for this disease in real patients? And could exercise benefit these patients?

“We were surprised that even exercise alone helped the mice recover from exertion more quickly,” says Wheeler. “Exercise plus antisense treatment had an even greater effect. But antisense alone was of no measurable benefit.”

While it seems normal for exercise to help patients suffering from muscle weakness, some doctors and researchers have wondered if it could also have the opposite effect and accelerate patient decline. The study by Wheeler and his colleagues suggests that this is not the case and that the effects of exercise could be beneficial to these patients and others with similar conditions.