Ataxia-telangiectasia mutated protein protects cardiac cells from stress by rewiring glucose metabolism

Abstract Introduction Pressure overload-induced cardiac hypertrophy is associated with increased reactive oxygen species (ROS), inducing DNA damage and activating the protein kinase Ataxia-Telangiectasia Mutated (ATM). Recently, ATM has been also involved in the regulation of several metabolic processes, but whether and how it affects cardiac metabolism is still poorly understood. Purpose We hypothesized that ATM might play crucial roles in the maintenance of cardiomyocyte metabolic homeostasis and in the development of cardiac dysfunction in response to pressure overload. Methods Atm+/+ and Atm homozygous mutated mice (Atm−/−) underwent transverse aortic constriction (TAC) or sham operation (sham). After one week (1w), sham and TAC mice were anesthetized, cardiac function and morphometry were analyzed, and gene expression reprogramming, cardiac histology, mitochondrial morphology were performed. Metabolic profiling was carried out through untargeted metabolomics (LC-MS/MS and GC/MS), mRNA and/or protein levels analysis to investigate glycolyis, pyruvate oxidation, Krebs cycle, aminoacid synthesis, gluconeogenesis and lipid oxidation. Results Atm genetic inactivation induced cardiomyocytes hypertrophy and fetal gene reprogramming in sham mice, with normal cardiac function and in the absence of fibrosis or mitochondrial dysfunction (Figure 1A). After TAC 1w, cardiac function was significantly decreased in Atm−/− mice, compared to Atm+/+ (Figure 1B). In both sham and TAC 1w Atm−/− mice, significant metabolic abnormalities were identified, including switching of glycolysis, reduction of pyruvate oxidation (Figure 1B), activation of aminoacid synthesis and accumulation of long and short-chain fatty acid conjugated with carnitine. Pyruvate accumulation was associated to a significant reduction of pyruvate carrier (MPC1-MPC2) and pyruvate dehydrogenase (PDH) levels in sham and TAC 1w Atm−/− mice. Conclusions ATM regulates gene expression, cardiomyocyte hypertrophy and cardiac responses to pressure overload, modulating cardiac metabolism and the profile of intracellular substrate utilization in the heart. Thus, ATM might represent a novel important player in the development of cardiac dysfunction and a novel therapeutic target. Figure 1 Funding Acknowledgement Type of funding source: Other. Main funding source(s): CP was supported by Ministero dell'Istruzione, Università e Ricerca Scientifica grant (2015583WMX) and Programma STAR grant by Federico II University and Compagnia di San Paolo. RP was supported by a research grant provided by the Cardiopath PhD program.