A University of Iowa study suggests that the prolonged fatigue after mild exercise that occurs in people with many forms of muscular dystrophy is distinct from the inherent muscle weakness caused by the disease.
Explain this trial?
Excessive fatigue after exercise is a hallmark of the neuromuscular disorders. In this trial, Dr. Kevin Campbell demonstrates the link between excessive fatigue after exercise and a decrease in nNOS (neuronal nitric oxide synthase) signaling in the sarcolemmal membrane. The sarcolemmal membrane surrounds the muscle cells. Working together with Dr. Chamberlain, Moore and Kobayashi, Dr. Campbell found a decrease in nNOS staining in muscle from across the dystrophies, taken from patients with Duchenne, limb girdle (LGMD21- FKRP dystroglycanopathy), Ullrich CMD and merosin deficient CMD.
What does decreased nNOS do?
nNOS is an enzyme that stimulates the production of cGMP. cGMP causes smooth muscle in the blood vessel walls to relax. In a normal muscle, after exercise, nNOS would typically cause an increase in cGMP which in turn would cause the walls of the blood vessels to relax, increasing blood flow to muscles post exercise. In the muscular dystrophies, including the CMDs, there is a decrease of nNOS which in turn leads to a decrease in cGMP. A decrease in cGMP means less blood flow to the tired muscle after exercise. This decreased blood flow helps explain the post exercise fatigue.
Is there a drug that targets nNOS or cGMP?
Viagra causes blood vessel wall relaxation by blocking the effects of PDE (phosphodiesterase). PDE is an enzyme that breaks down cGMP. Viagra blocks PDE and thereby increases cGMP which in turn causes blood vessel wall relaxation and increased blood flow.
Using the mdx mouse model (Duchenne), Dr. Campbell was able to show that Viagra decreased post exercise muscle edema. By decreasing muscle edema after exercise, this decreased the exacerbation of muscle damage that occurred during exercise with the dystrophic muscle.
What is the relevance to CMD?
Dr. Campbell demonstrated decreased staining of nNOS in muscle biopsy specimens from people with CMD. This shows that nNOS is diminished in the CMDs, and that drugs, such as Viagra, might play a role in decreasing post exercise fatigue.
What remains to be tested in “how beneficial is exercise and to what extent” in the CMDs? If exercise is beneficial, what is the role for decreasing post exercise fatigue?
Are there any other studies looking at exercise and muscle? There is another study published by Dr. Ronald Evans, that looked at using a drug, called AICAR that affects the AMPK-PPAR delta pathway. AMPK and PPAR delta are kinases that work during exercise to trigger gene expression that leads to modification of muscle fiber type and better cardiovascular and endocrine function, such as seen in endurance athletes. Dr. Evans was able to show that by using an AMPK agonist, called AICAR, he could induce an endurance muscle without the mouse having to exercise. The relevance of this study to CMD is unclear. The study demonstrates that it is possible with therapy to modify muscle to increase muscle endurance without needing to exercise the muscle. Given the fatigue post-exercise in CMD, this might be another target to increase muscle endurance without asking people with CMD to increase their exercise. Gone is the motto: “No pain, no gain”. Evans, Ronald et al. AMPK and PPAR delta Agonists are Exercise Mimetics. Cell 2008, August (134):1-11.