Influence of the PDE5 inhibitor tadalafil on redox status and antioxidant defense system in C2C12 skeletal muscle cells

Abstract

Phosphodiesterase type 5 inhibitors (PDE5Is), widely known for their beneficial effects onto male erectile dysfunction, seem to exert favorable effects onto metabolism as well. Tadalafil exposure increases oxidative metabolism of C2C12 skeletal muscle cells. A rise in fatty acid (FA) metabolism, requiring more oxygen, could induce a larger reactive oxygen species (ROS) release as a byproduct thus leading to a redox imbalance. The aim of this study was to determine how PDE5I tadalafil influences redox status in skeletal muscle cells to match the increasing oxidative metabolism. To this purpose, differentiated C2C12 skeletal muscle cells were treated with tadalafil and analyzed for total antioxidant capacity (TAC) and glutathione levels as marker of redox status; enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) engaged in antioxidant defense; and lipid peroxidation (TBARS) and protein carbonyls (PrCar) as markers of oxidative damage. Tadalafil increased total intracellular glutathione (tGSH), CAT, SOD, and GPx enzymatic activities while no changes were found in TAC. A perturbation of redox status, as showed by the decrease in the ratio between reduced/oxidized glutathione (GSH/GSSG), was observed. Nevertheless, it did not cause any change in TBARS and PrCar levels probably due to the enhancement in the antioxidant enzymatic network. Taken together, these data indicate that tadalafil, besides improving oxidative metabolism, may be beneficial to skeletal muscle cells by enhancing the enzymatic antioxidant system capacity.

The phosphodiesterase 5 inhibitor sildenafil decreases the proinflammatory chemokine IL-8 in diabetic cardiomyopathy: in vivo and in vitro evidence

“…Clinical evidence sustains a strong association between PDE5i use and reduced mortality rate and hospitalization in a cohort of T2D patients with attendant high cardiovascular risk [ 28 ]. PDE5 inhibition seems also to exert favorable effects by enhancing enzymatic antioxidant system capacity [ 29 ]. Of note, those effects were not achieved with other class of vasoactive drugs as prostaglandins.…”

Acute tadalafil administration increases plasma fatty acids without changes in the inflammatory response in healthy men

“…Supplementation of C2C12 myotubes with tadalafil influences the metabolism by improving FAs oxidation, as displayed by the increase of 3-OH acylCoA dehydrogenase and citrate synthase activities, respectively, which are involved in β-oxidation and the Krebs cycle (Sabatini et al, 2011). Recently, we have reported that such increase in oxidative metabolism may be beneficial to skeletal muscle cells by enhancing the enzymatic antioxidant system capacity (Duranti et al, 2017).…”

“…In our previous study, we have demonstrated that tadalafil improved oxidative capacity in C2C12 skeletal muscle cells in vitro, as displayed by an increased reliance on fat metabolism (Sabatini et al, 2011) accompanied by a better redox status (Duranti et al, 2017).…”

The Phosphodiesterase Type 5 Inhibitor Sildenafil Improves DNA Stability and Redox Homeostasis in Systemic Sclerosis Fibroblasts Exposed to Reactive Oxygen Species

“…TBARS levels were assayed by spectrophotometric analysis, as previously described [ 34 ]. The methodology calculates malondialdehyde (MDA) and other aldehydes generated by lipid peroxidation induced by hydroxyl free radicals.…”