Neutrophil-derived reactive oxygen species mediate doxorubicin-induced cardiotoxicity and skeletal myopathy.

Abstract

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. Although 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 cardioskeletal atrophy and dysfunction, including ejection fraction, stroke volume, and cardiac output. DOX-expanded neutrophils demonstrated constitutive production of reactive oxygen species (ROS), and elimination of the ROS-producing enzyme NOX2, but not myeloperoxidase, prevented DOX-induced cardioskeletal myopathy. Our findings underscore the pivotal role of neutrophil-derived ROS in driving DOX-induced cardiotoxicity and skeletal myopathy.DOX is a commonly used cancer treatment, but its severe side effects, limit its clinical use. This research highlights neutrophil-derived reactive oxygen species (ROS) production through the NOX2 complex as a key contributor to this myopathy, offering a potential therapeutic to protect against cardiotoxicity without compromising DOX's anticancer benefits. These insights open new avenues for safer, more effective cancer treatments.