Abstract 17659: Mitochondrial Pyruvate Transport is Required for the Cardiac Adaptation to Pressure Overload
Glucose and lactate are important fuel substrates for the heart, particularly during acute hemodynamic stresses such as pressure overload or following exercise training. Cytosolic pyruvate that is generated by glycolytic metabolism of glucose or by conversion of lactate is transported into mitochondria via the mitochondrial pyruvate carrier complex, which has two subunits, MPC1 and MPC2. MPC1 and MPC2 transcripts were repressed in mouse hearts 4 weeks after transverse aortic constriction (TAC). We therefore, generated cardiomyocyte-restricted MPC1 knockout mice (CMPC1-/-) to investigate the role MPC1 in maintaining cardiac function under resting conditions and following pressure overload. Loss of MPC1 resulted in degradation of MPC2 leading to functional inactivation of the MPC complex in CMPC1-/- mouse hearts. Cardiac function examined by echocardiography revealed that CMPC1-/- mice exhibited normal cardiac function by the age of 8 weeks but overt systolic dysfunction by the age of 18 weeks. Survival analysis showed that only 61% of CMPC1-/- mice remained alive at the age of 1-year relative to 98% of control mice. At the age of 8 weeks, heart weight (HW) and the heart weight to tibia ratio (HW/TL) were significantly increased, along with the transcriptional markers of pathological cardiac hypertrophy, NPPA, NPPB and Acta1. Substrate metabolism in isolated working hearts, revealed a 58% reduction in glucose oxidation in CMPC1-/- mice relative to control mice while palmitate oxidation was increased by 35%. CMPC1-/- mice were subjected to pressure overload at the age of 8 weeks. All CMPC1-/- mice died within a week after TAC surgery while all control mice survived. Thus mitochondrial pyruvate uptake is dispensable for normal cardiac development and function in non-stressed juvenile hearts although pathological cardiac hypertrophy and heart failure eventually ensues. Importantly, mitochondrial pyruvate uptake is essential for maintaining cardiac function in response to pressure overload.
Author Disclosures: Y. Zhang: None. J. Cox: None. J. Rutter: None. E. Abel: None.
- © 2016 by American Heart Association, Inc.