Effects of PDE5 inhibition on dystrophic muscle following an acute bout of downhill running and endurance training.

Lack of sarcolemma-localized neuronal nitric oxide synthase mu (nNOSμ) contributes to muscle damage and fatigue in dystrophic muscle. In this study, we examined the effects of compensating for lack of nNOSμ with a phosphodiesterase type 5 (PDE5) inhibitor in mice following downhill running and endurance training. Dystrophic mice () were treated with sildenafil citrate and compared with untreated and wild-type mice after an acute bout of downhill running and during a progressive low-intensity treadmill running program (5 days/wk, 4 wk). Magnetic resonance imaging (MRI) and spectroscopy (MRS) transverse relaxation time constant (T) of hindlimb and forelimb muscles were measured as a marker of muscle damage after downhill running and throughout training. The MRI blood oxygenation level dependence (BOLD) response and phosphorus MRS (P-MRS) data were acquired after stimulated muscle contractions. After downhill running, the increase in T was attenuated ( < 0.05) in treated and wild-type mice compared with untreated . During training, resting T values did not change in wild-type and mice from baseline values; however, the running distance completed during training was greater ( < 0.05) in treated (>90% of target distance) and wild-type (100%) than untreated (60%). The post-contractile BOLD response was greater ( < 0.05) in treated that trained than untreated , with no differences in muscle oxidative capacity, as measured by P-MRS. Our findings indicate that PDE5 inhibition reduces muscle damage after a single bout of downhill running and improves performance during endurance training in dystrophic mice, possibly because of enhanced microvascular function. This study examined the combined effects of PDE5 inhibition and exercise in dystrophic muscle using high-resolution magnetic resonance imaging and spectroscopy. Our findings demonstrated that sildenafil citrate reduces muscle damage after a single bout of downhill running, improves endurance-training performance, and enhances microvascular function in dystrophic muscle. Collectively, the results support the combination of exercise and PDE5 inhibition as a therapeutic approach in muscular dystrophies lacking nNOSμ.