514 ATAXIA TELANGIECTASIA MUTATED PROTEIN MODULATES GLUCOSE AND LIPID METABOLISM IN THE HEART

Abstract Background Ataxia Telangiectasia Mutated (ATM) protein kinase is the major sensor of DNA damage response (DDR) and oxidative stress, variously implicated in cellular metabolism. Previous studies on ATM functions heart have produced conflicting results. Here we hypothesized that might regulate cardiomyocyte metabolic homeostasis function. Methods Atm-mutated mice (Atm-/-) their wild-type littermates (Atm+/+) were used to assess effects inactivation hypertrophy, cardiac structure, function, DDR metabolism under sham conditions or after pressure overload by transverse aortic constriction (TAC). Results induced hypertrophy (FIG.1 A), fetal gene expression re-activation a specific metabolomic signature heart, characterized significant accumulation pyruvate, branched chain amino-acids, short-medium acyl-carnitines metabolites tricarboxylic acid cycle C, D),. Importantly, pyruvate was trapped cytosol because mitochondrial carriers suppressed enzymes process dysregulated. As consequence block, fatty acids oxidation inefficient resulted insulin resistance. Although these changes present constitutively Atm-/- mice, they amplified TAC, which rapidly failure B) mice. also increased basal TAC-induced genomic stress cardiomyocytes, as shown levels p-γ-H2AX, 8-oxodG glycosylase (OGG1/2) apurinic site nuclease (APE1). Cardiac loss (rise lactate succinate levels) brains, although different. Conclusions rewires cells inducing glycolysis oxidation. Combining metabolomic, phenotypes, deduce stimulates repair lesions protect against stress-induced dysfunction.