Metabolic alterations beyond fatty acid oxidation in PPAR alpha null mice hearts: Effect of workload and fasting

Subjects with fatty acid oxidation (FAO) defects are prone to cardiac decompensation during stress and fasting, yet the underlying mechanism is unclear. We examined the impact of these two conditions using PPARα null mice, a model of FAO defects. Using ex vivo perfusion and 13C-methodology, we assessed the metabolic and functional responses of working hearts from PPARα null mice and control C57BL/6 mice at two workloads. Hearts from PPARα null mice displayed an impaired response to a raise in preload as reflected by a 20% decline in aortic flow and cardiac efficiency, and enhanced lactate dehydrogenase release (2 folds) (p<0.05). At the metabolic level, these hearts showed the expected shift from FA (4-fold down) to carbohydrate (CHO: 2-fold up) (p<0.001) at both preloads, but their glycolytic flux rate expressed relative to that of pyruvate decarboxylation was significantly reduced (44%) at the higher preload, suggesting a mismatch between cytosolic and mitochondrial CHO metabolism. Further, we assessed the impact of a 24 h fasting period on the levels of citric acid cycle (CAC) intermediates and gene expression of glucose transporter GLUT4 and anaplerotic pyruvate carboxylase (PC) using real time PCR. In contrast to controls, fasting did not increase CAC intermediates levels in PPARα null mice hearts, despite resulting in higher mRNA levels for GLUT 4 and PC (p<0.001) in these mice, suggesting impaired anaplerosis. Collectively, our data highlight metabolic alterations in PPARα null mice hearts, beyond their lower FAO, which may be determinant for their response to increase workload and fasting. (Supported by NIH and CIHR.)