Effects of tadalafil on skeletal muscle tissue: exploring interactions and novel mechanisms of action

Beside its mechanical roles in controlling posture and locomotion, skeletal muscle system, the largest insulin and steroid hormones target tissue, plays a key role in influencing thermoregulation, secondary sexual characteristics, hormones metabolism, and glucose uptake and storage, as well as energetic metabolism. Indeed, in addition to insulin, several hor-mones influence the skeletal muscle metabolism/function and/or are influenced by skeletal muscles activity (i.e., physical exercise). Particularly, steroid hormones play a key role in modulating many biological processes in muscles, essential for overall muscle's function and homeostasis, both at rest and during all physical activities (i.e., physical exercise, muscular work). Phosphodiesterase type 5 (PDE5) is the enzyme engaged to hydrolyze cyclic guanosine monophosphate (cGMP) in inactive 5'-GMP form. Therefore, through the inhibition of this enzyme, the intracellular level of cGMP increases, and the cGMP-related cellular responses are prolonged. Different drugs inhibiting PDE5 (PDE5i) exist, and the commercially available PDE5i are sildenafil, vardenafil, tadalafil, and avanafil. The PDE5i tadalafil may influence cellular physiology and endocrine-metabolic pathways in skeletal muscles and exerts its functions both by activating the cell signaling linked to the insulin-related metabolic pathways and modulating the endocrine responses, protein catabolism and hormone -related anabolism/catabolism during and after physical exercise-related stress. Based on recent in-vivo and in-vitro find-ings, in this narrative review the aim was to summarize the available evidence describing the interactions between the PDE5i tadalafil and steroid hormones in skeletal muscle tissue and physical exercise adaptation, focusing our interest on their possible synergistic or competitive action(s) on muscle metabolism and function.

Automated summary

In addition to its mechanical roles, the skeletal muscle system plays a crucial role in thermoregulation, secondary sexual characteristics, hormone metabolism, glucose uptake and storage, and energetic metabolism. PDE5i drugs, such as tadalafil, can influence skeletal muscle physiology and endocrine-metabolic pathways by increasing the intracellular level of cGMP. These drugs can modulate insulin-related metabolic pathways and hormone responses, protein metabolism, and anabolism/catabolism during and after physical exercise-related stress.