Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy

Cardiomyocytes rely on metabolic substrates, not only to fuel cardiac output, but also for growth and remodeling during stress. Here we show that Mitochondrial Pyruvate Carrier (MPC) abundance mediates pathological cardiac hypertrophy. MPC abundance was reduced in failing hypertrophic human hearts, as well as the myocardium of mice induced to fail by angiotensin II or transverse-aortic constriction-induced. Constitutive knockout of cardiomyocyte MPC1/2 in mice resulted in cardiac hypertrophy and reduced survival, while tamoxifen-induced cardiomyocyte-specific reduction of MPC1/2 to the attenuated levels observed during pressure-overload was sufficient to induce hypertrophy with impaired cardiac function. Failing hearts from cardiomyocyte-restricted knockout mice displayed increased abundance of anabolic metabolites, including amino acids and pentose phosphate pathway intermediates and reducing cofactors. These hearts showed a concomitant decrease in carbon flux into mitochondrial tricarboxylic acid cycle intermediates, as corroborated by complementary 1,2-(13)C(2)-glucose tracer studies. In contrast, inducible cardiomyocyte overexpression of MPC1/2 resulted in increased tricarboxylic acid cycle intermediates, and sustained carrier expression during transverse-aortic constriction protected against cardiac hypertrophy and failure. Collectively, we demonstrate that loss of the MPC1/2 causally mediates adverse cardiac remodelling.