Tadalafil Alleviates Muscle Ischemia in Patients with Becker Muscular Dystrophy

The phosphodiesterase 5A inhibitor tadalafil restores normal blood flow regulation in exercising skeletal muscle of patients with Becker muscular dystrophy. 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. Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin’s rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective—causing functional muscle ischemia—in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3′,5′-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.