Abstract 18046: Ketogenic Diet Rescues Heart Failure Induced by Loss of the Mitochondrial Pyruvate Carrier 1

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Abstract

The healthy adult heart utilizes fatty acids, glucose, and lactate as primary fuels, and substrate flexibility is essential for maintaining cardiac function particularly under conditions of hemodynamic stress. Glucose and lactate metabolism requires conversion to pyruvate, which is then transported into mitochondria to be further oxidized. The mitochondrial pyruvate carrier (MPC) is the pyruvate transporter located on the mitochondrial inner membrane, the absence of which should severely restrict mitochondrial glucose/lactate oxidation. Cardiomyocyte-specific MPC1 knockout mice (cMPC1-/-) were generated to investigate the role of pyruvate transport on cardiac function. CMPC1-/- mice develop pathological cardiac hypertrophy at the age of 8 weeks and age-dependent heart failure by 18-weeks of age. Substrate utilization measured in isolated working hearts revealed decreased glucose oxidation and increased palmitate oxidation in cMPC1-/- mice. Ketone bodies are an important alternative cardiac fuel, particularly in failing hearts. CMPC1-/- mice were fed a ketogenic diet at different ages (3, 10 and 18 weeks old) to determine if ketones could rescue cardiac hypertrophy and heart failure induced by loss of MPC. Ketogenic diets induced at 3-weeks of age revealed that cardiac hypertrophy and heart failure was completely prevented in cMPC1-/- mice following up to 15 weeks of ketogenic feeding. Initiating ketogenic diet in 10-week- old cMPC1-/- mice after compensated cardiac hypertrophy developed, led to regression of LV hypertrophy and maintenance of cardiac function after 8 weeks of ketogenic diet feeding. cMPC1-/- mice developed heart failure at the age of 18 weeks and 3 weeks of ketogenic feeding, initiated after heart failure developed, significantly improved cardiac structure and function manifested by decreased left ventricle mass and increased ejection fraction. Pyruvate and lactate accumulation in cMPC1-/- hearts was reversed by ketogenic diets. In conclusion, ketogenic diets rescue cardiac hypertrophy and heart failure in MPC1 deficient hearts, supporting a model in which substrate limitation mediates the cardiomyopathy that develops in response to impaired pyruvate oxidation.

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