ATM: a protein involved in glucose and lipid metabolism in the heart

Abstract Backround Post-mitotic cells, such as neurons and cardiomyocytes, cannot repair DNA lesions with DNA replication and rely for their survival on efficient sensors and effectors that orchestrate the DNA damage response (DDR). The Ataxia Telangiectasia Mutated (ATM) protein kinase is the most important sensor of oxidative stress and the DNA damage response (DDR) and is implicated in cellular metabolism. It is believed that while transient DNA damage and DDR can temporarily improve cardiovascular function, persistent activation of DDR (and ATM) might promote the onset and development of heart failure (HF). Purpose We hypothesised that ATM might control and regulate energy metabolism in the heart under stress to promote DNA repair. Methods We analyzed the effects of ATM inactivation on cardiomyocyte hypertrophy, cardiac function, DDR and metabolism in hearts from wild-type (Atm+/+) or Atm-mutated (Atm-/-) mice under sham conditions or after pressure overload by transverse aortic constriction (TAC). Results ATM inactivation in Atm-/- mice induced cardiomyocyte hypertrophy, fetal gene expression re-activation and a specific metabolomic signature in the heart, characterized by significant accumulation of pyruvate, branched chain amino-acids, short-medium acyl-carnitines and metabolites of tricarboxylic acid cycle. The levels of the glycolytic enzymes, hexokinase-2 (HK2) and phosphofructokinase (PFK), were elevated. pyruvate was trapped in the cytosol because mitochondrial carriers were suppressed and the enzymes that process pyruvate were dysregulated. Because of pyruvate metabolic block, fatty acids oxidation was inefficient and resulted in the accumulation of acyl-carnitines and insulin resistance. These metabolic changes were amplified by TAC, which rapidly induced heart failure in Atm-/- mice. ATM inactivation also increased basal and TAC-induced genomic stress in cardiomyocytes, as shown by the levels of p-γ-H2AX, 8-oxodG glycosylase (OGG1/2) and apurinic site nuclease (APE1). These results prove that ATM rewires the metabolism of cardiac cells by inducing glycolysis and fatty acids oxidation. ATM stimulates glycolysis to repair DNA lesions and protect the heart against stress-induced dysfunction. The metabolic block due to ATM inactivation accelerates heart failure. Conclusions Our data suggest that ATM favors the metabolic flexibility of the heart by stimulating glucose entry and balancing glucose catabolism with fatty acid oxidation, thus preventing mechanical stress-induced cardiac systolic dysfunction.