Genetic treatment plus exercise reverses fatigue in mice with muscle wasting disease

"It's encouraging that exercise makes a noticeable difference on its own and in combination with a genetic treatment specifically tailored for the disease," says Thurman M. Wheeler, MD, an investigator in the 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 wasting and progressive weakness. Patients with DM1 report that chronic fatigue is the most debilitating symptom of their condition, although the biological underpinning of this effect is not known. Wheeler and his colleagues wanted to test the value of exercise in reversing 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 an expanded microsatellite CUG repeat. The researchers used mice genetically engineered to carry the same defect and treated some of them with an antisense oligonucleotide, which is essentially a strand of genetic material that sticks to RNA to repair specific gene defects.

Then they studied the effects of exercise on old mice with the gene defect who received only the oligonucleotide, some that were only compelled to exercise, some that had both the treatment and exercised, and a group that received a placebo (a saline solution). They compared the post-exercise activity levels of mice in each of those arms of the trial. They also measured the responses of young mice with the defect who just received the placebo. The mice's activity was measured using a special type of enclosure that records the mouse's movement.

This study provides preliminary answers to at least two questions: How effective should scientists expect gene therapy for this disease will be in actual patients? And could exercise benefit such patients?

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

While it seems like common sense that exercise would help patients suffering from muscle weaknesses, some clinicians and researchers wondered if it could also have the opposite effect and actually hasten patients' decline. Wheeler and his colleagues' study suggests that is not the case and that the effects of exercise could be beneficial to these patients and others with similar conditions.

Wheeler's co-authors included colleagues at the MGH Department of Neurology as well as researchers from Beth Israel Deaconess Medical Center.

The Elaine and Richard Slye Fund, Muscular Dystrophy 525 Association and the National Institutes of Health supported the work.