Abstract 12168: Pi3kγ is a Key Modulator of Cardiac Metabolism Rewiring Occurring in Doxorubicin-Treated Mice

Introduction: Doxorubicin (DOX) is a potent chemotherapeutic drug, whose use is hampered by the onset of long-term cardiotoxicity and lack of effective therapeutic approaches. Recently, metabolic perturbations have emerged as an early predictor factor of cardiac dysfunction, but how DOX affects cardiac metabolism is still unknown. We have previously demonstrated that phosphoinositide 3-kinase γ (PI3Kγ) is a major driver of DOX-evoked cardiotoxicity through mitophagy inhibition and accumulation of dysfunctional mitochondria. Hypothesis: Here we sought to explore the role of PI3Kγ in modulating cardiac metabolism upon DOX administration. Methods: Metabolomic analysis, glycolysis and oxidative phosphorylation were measured in whole hearts from wild-type (WT) and knock-in mice expressing a kinase-inactive PI3Kγ (kinase-dead; KD) treated with DOX (4 mg/kg on day 0, 7 and 14). Similar analyses were performed in WT and KD hearts infected with AAV9-shATG7 to explore the role of autophagy. Moreover, glucose uptake and GLUT-4 expression on the plasma membrane were measured in WT and KD neonatal mouse cardiomyocytes (NMCs) exposed to 1μM DOX. Results: Metabolomic analysis revealed an increased level of succinate and malic acid in DOX-treated hearts, suggesting defects in the TCA cycle. In agreement, DOX promotes the accumulation of metabolites normally catabolised in the TCA cycle, such as aminoacids and pyruvate, indicating a severe mitochondria dysfunction. Accordingly, fatty acid oxidation and electron transport chain activity were impaired in DOX-treated hearts at day 3 and exacerbated at day 42 after DOX. At the same time, glycolysis was upregulated. These changes were prevented in KD animals. Interestingly, upon autophagy inhibition, KD mice lost their cardioprotection at the mitochondrial level, but they still failed to upregulate glycolysis. This suggests a new autophagy-independent mechanism through which PI3Kγ regulates glucose utilisation. In agreement with the pharmacological and genetic inhibition of PI3Kγ abrogates glucose uptake in NMCs and normalises the plasma membrane exposure of GLUT-4. Conclusions: Overall, these results promote PI3Kγ as a master regulator of metabolic rewiring occurring in DOX-treated cardiomyocytes.