Neutrophil-derived Reactive Oxygen Species Mediate Doxorubicin-induced Cardiotoxicity and Skeletal Myopathy

Doxorubicin (DOX), an effective chemotherapy, exhibits a narrow therapeutic index and detrimental adverse effects involving muscle atrophy and dysfunction. The precise mechanisms underlying DOX-mediated myopathy are not fully understood. While the contribution of inflammation is well appreciated, the mechanisms by which inflammatory cells mediate muscular pathologies remain to be identified. In this study, we characterized the dynamics of neutrophil responses during DOX treatment. DOX administration induced expansion of neutrophils in the heart, spleen, and muscle of mice. Depletion of these cells with anti-Ly6G antibodies ameliorated DOX-mediated cardio-skeletal atrophy and dysfunction, including ejection fraction, stroke volume, and cardiac output. DOX-expanded neutrophils demonstrated constitutive production of ROS, and elimination of the ROS-producing enzyme NOX2, but not myeloperoxidase, prevented DOX-induced cardio-skeletal myopathy. Our findings underscore the pivotal role of neutrophil-derived ROS in driving DOX-induced cardiotoxicity and skeletal myopathy.