Unveiling the Metabolic Changes Underlying Doxorubicin-Induced Cardiotoxicity: Insights into Cardiac Lipotoxicity

Doxorubicin (DOX) is a member of the anthracycline class of chemotherapeutic agents, widely employed in oncology for its potent anticancer properties. However, its clinical use is hampered by dose-dependent cardiotoxicity, which can eventually lead to irreversible cardiac dysfunction and heart failure due to the lack of adequate preventive approaches. Notably, metabolic perturbations have emerged as early predictor factors of cardiac dysfunction. However, how DOX affects cardiac metabolism remains poorly understood. This project aims to characterize how DOX treatment affects cardiac metabolism and assess the underlying molecular mechanisms behind DOX-induced cardiotoxicity. Mitochondrial dysfunction is a defining feature of DOX-induced cardiotoxicity, prompting our investigation into whether DOX exerts cardiotoxicity by perturbating cardiac mitochondrial metabolism, thereby inducing mitochondrial lipid accumulation and lipotoxicity. To this end, we measured glycolytic activity, plasma membrane GLUT-4 expression, oxidative phosphorylation efficiency, glucose uptake rate and intracellular lipid levels in neonatal mouse cardiomyocytes (NMCs) exposed to 1uM DOX. Additionally, we assessed tissue lipid content in whole hearts from mice treated with DOX (4mg/kg on days 0, 7, and 14) using Oil Red O (ORO) staining. Overall, the results of this thesis demonstrate that DOX promotes a maladaptive cardiac metabolic switch from an oxidative metabolism towards increased glucose usage. Moreover, an imbalanced fatty acid uptake and utilization eventually leads to intracellular lipid buildup and consequent lipotoxicity.