Apocynin prevents cigarette smoking-induced loss of skeletal muscle mass and function by preserving proteostatic signalling

Background and Purpose Skeletal muscle dysfunction is a major comorbidity of COPD. It has been postulated that this type of muscle dysfunction may be a direct consequence of oxidative insults evoked by CS exposure. The present study examined the effect of a potent Nox inhibitor and ROS scavenger, apocynin on CS-induced muscle dysfunction. Experimental Approach Male BALB/c mice were exposed to either room air (sham) or CS generated from 9 cigarettes per day, 5 days a week for 8 weeks with or without apocynin treatment (5 mg·kg-1 w/v, intraperitoneal injection). C2C12 myotubes exposed to either hydrogen peroxide (H2O2) or water-soluble cigarette smoke extract (CSE) with or without apocynin (500 nM), was set up as an experimental model in vitro. Key Results Eight weeks of CS exposure caused muscle dysfunction in mice; evidenced by a 10% loss in muscle mass and 54% loss in strength of tibialis anterior which were prevented by apocynin administration. In C2C12 myotubes, direct exposure to H2O2 or CSE caused myofiber wasting, which was associated with ~50% loss in muscle-derived insulin-like growth factor (IGF)-1 and 2-fold induction of Nox2, independent of cellular inflammation. The expression of myostatin and MAFbx, negative regulator of muscle mass, were upregulated under H2O2 but not CSE conditions. Apocynin treatment completely attenuated CSE-induced Nox2 expression, preserving muscle-derived IGF-1 expression and signaling pathway downstream of mammalian target of rapamycin (mTOR), thereby preventing myofiber wasting. Conclusion and Implications Targeted pharmacological inhibition of Nox-derived ROS may alleviate the lung and systemic manifestations in smokers with COPD.