Doxorubicin (DOX) is an effective antitumor agent used in cancer treatment. However, its clinical use is limited due to cardiotoxicity. Indeed, the side effects of DOX are irreversible and include the development of cardiomyopathy and ultimately congestive heart failure. Although many studies have investigated the events leading to DOX-induced cardiotoxicity, the mechanisms responsible for DOX-induced cardiotoxicity remain unknown. In general, evidence suggests that DOX-induced cardiotoxicity is associated with an increased generation of reactive oxygen species and oxidative damage, leading to the activation of cellular proteolytic systems. In this regard, the autophagy/lysosomal proteolytic system is a constitutively active catabolic process that is responsible for the degradation of both organelles and cytosolic proteins. We tested the hypothesis that systemic DOX administration results in altered cardiac gene and protein expression of mediators of the autophagy/lysosomal system. Our results support this hypothesis, as DOX treatment increased both the mRNA and protein levels of numerous key autophagy genes. Because exercise training has been shown to be cardioprotective against DOX-induced damage, we also determined whether exercise training before DOX administration alters the expression of important components of the autophagy/lysosomal system in cardiac muscle. Our findings show that exercise training inhibits DOX-induced cardiac increases in autophagy signaling. Collectively, our results reveal that DOX administration promotes activation of the autophagy/lysosomal system pathway in the heart, and that endurance exercise training can be a cardioprotective intervention against myocardial DOX-induced toxicity.
Keywords: anthracyclines; cardioprotection; oxidative damage; proteolysis; reactive oxygen species.