Mitochondrial Pyruvate Carriers are Required for Myocardial Stress Adaptation

In addition to fatty acids, glucose and lactate are important myocardial substrates under physiological and stress conditions. They are metabolized to pyruvate that enters mitochondria via the mitochondrial pyruvate carrier (MPC) for citric acid cycle (CAC) metabolism. Here, we show that MPC-mediated mitochondrial pyruvate utilization is essential for the partitioning of glucose-derived cytosolic metabolic intermediates, which modulate myocardial stress adaptation. Mice with cardiomyocyte-restricted deletion of subunit 1 of MPC (cMPC1(−/−)) developed age-dependent pathologic cardiac hypertrophy, transitioning to a dilated cardiomyopathy and premature death. Hypertrophied hearts accumulated lactate, pyruvate, and glycogen and displayed increased protein O-GlcNacylation (O-GlcNAc), which was prevented by increasing availability of non-glucose substrates in vivo by ketogenic (KD) or high-fat (HFD) diets, which reversed the structural, metabolic and functional remodeling of non-stressed cMPC1(−/−) hearts. While concurrent short-term KD did not rescue cMPC1(−/−) hearts from rapid decompensation and early mortality following pressure overload, 3-week of KD prior to TAC was sufficient to rescue this phenotype. Together, our results highlight the centrality of pyruvate metabolism to myocardial metabolism and function.