In studies with genetically engineered mice that showed this form of fatigue after mild exercise, the researchers found that an enzyme called neuronal nitric oxide synthase (nNOS) is not present at its normal location in the membrane surrounding muscle cells. This means the blood vessels that supply active muscles do not relax normally and the animals experience fatigue after very mild exercise.
Howard Hughes Medical Institute researcher Kevin P. Campbell led a research team from the University of Iowa that reported its findings in the November 27, 2008, issue of the journal Nature.
In identifying the mechanism for this specific form of fatigue, the researchers found that the fatigue can be alleviated pharmacologically. When the scientists administered Viagra-like drugs to the mice with muscular dystrophy, they noticed an increase in their ability to move, as well as a dramatic increase in their activity after mild exercise. The treated mice were two to four times more active than untreated mice with muscular dystrophy. Prior to treatment, the same mice would become virtually inert after a short burst of low-intensity activity.
Nitric oxide signaling stimulates the generation of cGMP, a phosphodiester, which leads to a cascade of effects that culminates in the dilation of blood vessels. A phosphodiesterase (PDE) breaks down cGMP, limiting its duration to signal the vessels to dilate. Viagra enhances nitric oxide signaling by inhibiting the PDE from breaking down cGMP, allowing for prolonged vasodilation upon nitric oxide signaling. Further research involving longer-acting versions of PDE inhibitors could lead to the first therapies to improve the physical endurance of patients with muscular dystrophy and improve their quality of life, said Campbell. “Even with patients who have milder dystrophies, when they visit our lab and walk around for a short time become fatigued,” he said.
The provocative results might have implications for treatment of other conditions, such as multiple sclerosis, chronic fatigue syndrome, and even the aging-related muscle weakness that can lead to dangerous falls, Campbell speculated.