The Maintenance Ability and Ca2+ Availability of Skeletal Muscle are Enhanced by Sildenafil

Abstract

Sildenafil relaxes vascular smooth muscle cells, and is used to treat pulmonary artery hypertension as well as erectile dysfunction. However, the effectiveness of sildenafil on skeletal muscle and the benefit of its clinical use have been controversial, and most studies have focused primarily on tissues and organs from disease models, without cellular examinations. Here, the effects of sildenafil on skeletal muscle at the cellular level were examined using mouse primary skeletal myoblasts (the proliferative forms of skeletal muscle stem cells) and myotubes along with single-cell Ca2+ imaging experiments and cellular and biochemical examinations. The proliferation of the skeletal myoblasts was enhanced by sildenafil, without dose-dependency. In the skeletal myotubes, sildenafil enhances the activity of ryanodine receptor 1, an internal Ca2+ channel, and Ca2+ movements that promote skeletal muscle contraction, possibly due to an increase in the resting cytosolic Ca2+ level and a unique microscopic shape in the myotube membranes. Therefore, these results suggest that the maintenance ability of skeletal muscle mass and the contractility of skeletal muscle could be improved by sildenafil via enhancing the proliferation of skeletal myoblasts and increasing the Ca2+ availability of skeletal myotubes, respectively.