Celecoxib enhances explosive exercise capacity in hypoxic mice and attenuates glutathione-associated oxidative stress in hypoxic C2C12 cells

Under hypoxic conditions, exercise capacity declines, accompanied by the significant activation of the arachidonic acid (AA) metabolism. The AA metabolism pathway has been confirmed to participated in the regulation of hypoxic inflammation. However, the relationship between hypoxia and AA metabolism remains largely unclear and whether targeting AA metabolism represents an effective strategy to improve exercise capacity is not clear. Celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, has been showed to effectively inhabit AA metabolism with minimal side-effects. In this study, celecoxib was used to inhibit AA metabolism in both murine and cellular models, and COX-2-specific siRNA was employed in cells. COX-2 expression was assessed by quantitative PCR (qPCR) and Western blots (WB), and the effect of celecoxib on exercise capacity was evaluated. Additionally, RNA-Seq and Seahorse XF assays were performed to further investigate the underlying mechanism. We found that celecoxib-mediated inhibition of COX-2 improved could improve explosive exercise capacity of hypoxic mice. Moreover, celecoxib could reactivate the GSTA pathway in hypoxic cells, attenuated reactive oxygen species (ROS) damage, and decrease oxygen and energy consumption. Our study reveals that celecoxib, via selective targeting of COX-2, represents a novel therapeutic approach to enhancing explosive exercise capacity under hypoxic conditions.