Viagra variants could beat muscle fatigue

The extreme fatigue that muscular dystrophy patients suffer after gentle exercise could be treated with longer-acting variants of sildenafil (Viagra), US scientists say - if a molecular mechanism newly revealed in mice can be translated to humans.

Kevin Campbell at the University of Iowa and colleagues studied mouse models of Duchenne muscular dystrophy - one of a group of disorders that cause muscles to gradually waste away. The mice Campbell studied had weak muscles, but not weak enough to account for their fatigue after exercise. 

Looking for another explanation, the researchers found that the tired mice lacked a key signalling molecule in the membrane of their muscle cells: neuronal nitric oxide synthase (nNOS), which triggers blood vessel dilation and increases blood flow to exercising muscle. In healthy muscle, nNOS releases nitric oxide during exercise. This in turn triggers the release of cGMP (cyclic guanosine monophosphate), which relaxes smooth muscle in blood vessels, causing the vessels to dilate.

Campbell then showed that artificially boosting blood vessel dilation - by blocking molecules that degrade cGMP - could counter the fatigue effect. He did this by treating the mice with PDE5 inhibitors - the family of drugs that includes sildenafil (Viagra), which works by blocking cGMP degradation.  

Patients with a wide variety of neuromuscular diseases have reduced nNOS levels, suggesting a common mechanism of fatigue that could be treated with PDE5 inhibitors, says Campbell. Drugs such as Viagra already on the market have been developed to be fairly short acting, so wouldn’t be particularly useful to treat muscular dystrophy. ’We’ve been in contact with several companies who have made a lot of these drugs because of their main indication [erectile dysfunction], and they have ones that are long-acting,’ says Campbell. ’We’re planning to look at some of these to find out if they’d be useful.’

James Mitchell Crow

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