Abstract 13211: Loss of Mitochondrial Pyruvate Carrier 1 in Cardiomyocytes Leads to Compensated Cardiac Hypertrophy in Non-stressed Hearts

Although normal adult hearts utilize fatty acid oxidation to generate the majority of ATP, glucose and lactate remain important fuel substrates, in response to hemodynamic stress such as pressure overload hypertrophy and in response to exercise training. Glucose and lactate are converted to pyruvate in the cytosol and then transported into mitochondria to be oxidized. Pyruvate enters mitochondria via a recently described transport complex - the mitochondrial pyruvate carrier that has two subunits, MPC1 and MPC2. The role of pyruvate uptake in regulating cardiac function and metabolism is incompletely understood. Thus, we generated cardiomyocyte-restricted MPC1 knockout mice (CMPC1-/-) to address this question. Loss of MPC1 resulted in degradation of MPC2 leading to functional inactivation of the MPC complex in CMPC1-/- mouse hearts. CMPC1-/- mice showed normal heart weight (HW), heart weight to body weight ratio (HW/BW) and heart weight to tibia length ratio (HW/TL) compared to their control littermates at the age of 4 weeks. Cardiac function examined by echocardiography also revealed that CMPC1-/- mice exhibited normal ventricular diastolic and systolic volumes, ejection fraction (EF) and cardiac mass compared to control mice. At the age of 8 weeks, both male and female CMPC1-/- mice exhibited compensated cardiac hypertrophy with preserved cardiac function as determined by echocardiography. Heart weights (HW) was increased by 1.41 fold (p<0.05) and HW normalized to tibia length, increased by 1.63 fold (p<0.01) in 8 week-old CMPC1-/- mice. Gene expression markers characteristic for pathological cardiac hypertrophy (NPPA, NPPB and Acta1) were also increased in 8 week-old CMPC1-/- hearts. Substrate metabolism measured in isolated working hearts, showed that glucose oxidation was significantly decreased by 58% (p=0.003) in CMPC1-/- mice relative to control mice. These data suggest that mitochondrial pyruvate uptake although dispensable for normal cardiac function in non-stressed hearts of young mice, reveals an important mechanism by which an imbalance between glycolysis and glucose oxidation may activate maladaptive hypertrophic signaling pathways in the myocardium.