Research ArticleMuscular Dystrophy

Tadalafil Alleviates Muscle Ischemia in Patients with Becker Muscular Dystrophy

Science Translational Medicine  28 Nov 2012:
Vol. 4, Issue 162, pp. 162ra155
DOI: 10.1126/scitranslmed.3004327

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A Shot in the Arm for Muscular Dystrophy

Becker muscular dystrophy (BMD), characterized by progressive skeletal muscle wasting, is caused by mutations in the muscle protein dystrophin. Preclinical research in the dystrophin-deficient mdx mouse model of a related disease Duchenne muscular dystrophy shows that inhibitors of phosphodiesterase 5 (PDE5)—which boosts guanosine 3′,5′-monophosphate (cGMP), the downstream target of nitric oxide (NO) in vascular smooth muscle—alleviate some features of the dystrophic phenotype including vasospasm of skeletal muscle microvessels that can lead to muscle injury and fatigue. The challenge is to determine whether these compelling results in mice can be translated to benefit human patients with muscular dystrophy. In a new study, Martin et al. assessed exercise-induced attenuation of reflex sympathetic vasoconstriction in the muscles of 10 patients with BMD and 7 age-matched healthy male controls. This is a protective mechanism that optimizes perfusion of skeletal muscle to meet the metabolic demands of exercise. Reflex vasoconstriction was induced by simulated orthostatic stress and was measured as the decrease in forearm muscle oxygenation using near-infrared spectroscopy. The authors took the measurements when the forearm muscles were rested or lightly exercised in the form of a rhythmic handgrip. First, the investigators showed that exercise-induced attenuation of reflex vasoconstriction was defective in 9 of 10 patients with BMD in whom the common dystrophin mutations disrupt targeting of neuronal NO synthase (nNOS) to the muscle sarcolemma (the response was preserved in one patient in whom nNOS was localized to the muscle sarcolemma). Then, in a double-blind randomized placebo-controlled crossover trial, the authors showed that normal blood flow regulation was fully restored in eight of nine patients by a single oral 20-mg dose of the drug tadalafil, a specific PDE5 inhibitor. These findings support an essential role for sarcolemmal nNOS in modulating sympathetic vasoconstriction in exercising human skeletal muscles and implicate PDE5 inhibition as a putative therapeutic strategy for treating BMD.