Sildenafil Increases Muscle Protein Synthesis and Reduces Muscle Fatigue

Abstract

Reductions in skeletal muscle function occur during the course of healthy aging as well as with bedrest or diverse diseases such as cancer, muscular dystrophy, and heart failure. However, there are no accepted pharmacologic therapies to improve impaired skeletal muscle function. Nitric oxide may influence skeletal muscle function through effects on excitation-contraction coupling, myofibrillar function, perfusion, and metabolism. Here we show that augmentation of nitric oxide-cyclic guanosine monophosphate signaling by short-term daily administration of the phosphodiesterase 5 inhibitor sildenafil increases protein synthesis, alters protein expression and nitrosylation, and reduces fatigue in human skeletal muscle. These findings suggest that phosphodiesterase 5 inhibitors represent viable pharmacologic interventions to improve muscle function.

Sildenafil improves skeletal muscle oxygenation during exercise in men with intermittent claudication

“…Percival et al (38) showed that a 14-wk treatment with sildenafil reduced respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy. In humans, a recent study documented that sildenafil administration for 8 consecutive days nearly doubled skeletal muscle protein synthesis and reduced muscle fatigue in healthy subjects (45). On the basis of these observations, future studies are needed to verify the long-term consequences of regular sildenafil administration in patients with IC.…”

The Maintenance Ability and Ca 2+ Availability of Skeletal Muscle are Enhanced by Sildenafil

“…23,[25][26][27][28][29] In addition, unlike smooth muscle, most sildenafil studies on skeletal muscle were conducted at macroscopic levels, such as physiological aspects of tissues or Figure 4 Ca 2+ movement in primary skeletal myotubes. Caffeine (a), which is a direct RyR1 agonist or KCl (b), a membrane depolarizer, was applied to myotubes treated with sildenafil, and Ca 2+ movement from the SR to cytosol in myotubes was measured.…”

“…Sildenafil lowers blood pressure by dilating blood vessels, [20][21][22] it improves skeletal muscle oxygenation during exercise in patients with intermittent claudication, 29 and it ameliorates skeletal muscle fatigue in a mouse DMD model and in healthy men. 23,24 …”

“…[20][21][22] However, the effectiveness of sildenafil on skeletal muscle and the benefit of its clinical use have been controversial-positive, negative or no effect. Sildenafil reduces fatigue of the knee extensors in generally healthy males 23 and decreases exaggerated skeletal muscle fatigue in a mouse model of Duchenne muscular dystrophy (DMD). 24 Sildenafil enhances the grip-strength of skeletal muscle in mice 25 and alleviates exercise-induced skeletal muscle ischemia in boys with DMD.…”

Nitric Oxide in Health and Physical Performance: Considering the Molecule 2 Nitrooxy Ethyl 2 Amino 3 Methylbutanoate

“…These agents include the sublingual and transdermal nitrates, intravenous propionyl-L-carnitine, intravenous L-arginine, and other medications used for the treatment of erectile dysfunction (e.g., phosphodiesterase-5 inhibitors). Related to the latter, although specifically prescribed for purposes of improving erectile function, evidence indicates the potential role of a phosphodiesterase-5 inhibitor (Sildenafil) to impact outcomes related to physical performance and adaptations to regular exercise (Hsu et al, 2006;Rinaldi et al, 2013;Sheffield-Moore et al, 2013). This fact suggests the likelihood that phosphodiesterase-5 inhibitors are now being used within the athletic doping world.…”