NIH Research Matters
November 3, 2008
Insight into Post-Exercise Fatigue in Muscular Dystrophy
Scientists have identified a disrupted molecular pathway that leads to fatigue after even mild physical exertion in mice with muscular dystrophy. This fatigue can be relieved by giving the animals a drug that bypasses the disruption. The finding may lead to a better understanding of the post-activity exhaustion that strikes many people who have neuromuscular disorders.
Muscular dystrophy is a group of more than 30 distinct genetic conditions characterized by increasing weakness and breakdown of the skeletal muscles that control movement. The most common forms in children are Duchenne and Becker muscular dystrophies, which primarily affect boys. Recent evidence suggests that in both of these disorders a protein called neuronal nitric oxide synthase (nNOS) is missing from its usual location in muscle cells. Normally found at the muscle cell membrane, nNOS helps signal blood vessels to widen, increasing blood flow to active muscles.
Now, a new study reports that nNOS deficiencies at the muscle cell membrane play a key role in post-exercise muscle fatigue in mice. Dr. Kevin Campbell of the University of Iowa and his colleagues found that this temporary lack of energy differs from the general muscle weakness inherent to muscular dystrophy. The research, described in the advance online edition of Nature on October 26, 2008, was funded in part by NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Neurological Disorders and Stroke (NINDS) and National Center for Research Resources (NCRR).
The researchers examined activity levels in normal mice and in mice with nNOS deficiencies before and after a mild treadmill exercise. Before exercise, all the mice—even those with muscular dystrophy—displayed normal activity. After exercise, however, mice with nNOS deficiencies at the muscle cell membrane had significantly less activity.
Blood vessel imaging showed that, after exercise, the muscles of nNOS-deficient mice had narrowed vessels and reduced blood flow, potentially explaining the mice's inability to quickly recover from mild physical exertion. The researchers then treated the nNOS-deficient mice with a panel of drugs that promote dilation of blood vessels. They found that only 2 of the drugs—both of which compensate for the defective nNOS signaling—successfully alleviated post-exercise fatigue in the animals.
Because more than 60% of all patients with neuromuscular disease experience severe fatigue, the researchers next examined muscle biopsies from 425 people with many different forms of muscular dystrophy. In more than 75% of the samples, nNOS was either reduced or undetectable at the muscle cell membrane, suggesting a similar mechanism of fatigue in these neuromuscular diseases.
Although further study is needed, this research suggests that it may be possible to decrease the fatigue and muscle damage brought on by physical activity in people with muscular dystrophy by altering the nNOS signaling pathway.
—by Vicki Contie
NIH Research Matters
Bldg. 31, Rm. 5B64A, MSC 2094
Bethesda, MD 20892-2094
About NIH Research Matters
Harrison Wein, Ph.D., Editor
Vicki Contie, Assistant Editor
NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.