Sildenafil increases muscle protein synthesis and reduces muscle fatigue

Melinda Sheffield-Moore, John E Wiktorowicz, Kizhake V Soman, Christopher P Danesi, Michael P Kinsky, Edgar L Dillon, Kathleen M Randolph, Shannon L Casperson, Dennis C Gore, Astrid M Horstman, James P Lynch, Barbara M Doucet, Joni A Mettler, Jeffrey W Ryder, Lori L Ploutz-Snyder, Jean W Hsu, Farook Jahoor, Kristofer Jennings, Gregory R White, Susan D McCammon, William J Durham, Melinda Sheffield-Moore, John E Wiktorowicz, Kizhake V Soman, Christopher P Danesi, Michael P Kinsky, Edgar L Dillon, Kathleen M Randolph, Shannon L Casperson, Dennis C Gore, Astrid M Horstman, James P Lynch, Barbara M Doucet, Joni A Mettler, Jeffrey W Ryder, Lori L Ploutz-Snyder, Jean W Hsu, Farook Jahoor, Kristofer Jennings, Gregory R White, Susan D McCammon, William J Durham

Abstract

Reductions in skeletal muscle function occur during the course of healthy aging as well as with bed rest 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.

Keywords: exercise; metabolism; protein S-nitrosylation; translational research.

© 2013 Wiley Periodicals, Inc.

Figures

Figure 1
Figure 1
Study time line.
Figure 2
Figure 2
Effects of sildenafil treatment on skeletal muscle function. (A) Isometric strength of knee extensors (mean percent baseline day ± standard error (SE)) after 8 days of treatment, determined using dynamometry. (B) Isokinetic (120° per second) strength of knee extensors (mean percent baseline day ± SE) after 8 days of treatment, determined using dynamometry. (C) Successful repetitions (mean percent baseline day ± SE) during fatiguing isokinetic (120° per second) contractions after 8 days of treatment. *p = 0.016 vs. placebo, unpaired t‐test, N = 6 placebo, 5 sildenafil. Individual numbers of successful repetitions before (pre) and after (post) treatment for those receiving placebo (upper panel) and sildenafil (lower panel) are shown at right.
Figure 3
Figure 3
Effects of sildenafil treatment on skeletal muscle proteome. (A) Skeletal muscle protein synthesis (mean ± SE) after 8 days of treatment, determined using the precursor‐product approach to determine fractional synthesis rate. *p = 0.004 vs. placebo, unpaired t‐test, N = 6 placebo, 5 sildenafil. Canonical (B) and functional (C) pathways differentially affected by sildenafil and placebo, determined using Ingenuity Pathways Analysis (IPA) of protein expression in skeletal muscle biopsy samples (top 6 pathways shown). Canonical (D) and functional (E) pathways differentially affected by sildenafil and placebo, determined using IPA of protein S‐nitrosylation in skeletal muscle biopsy samples (top six pathways shown).

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