title: Parallel activation of mitochondrial oxidative metabolism with increased cardiac energy expenditure is not dependent on fatty acid oxidation in pigs.
abstract: Steady state concentrations of ATP and ADP in vivo are similar at low and high cardiac workloads; however, the mechanisms that regulate the activation of substrate metabolism and oxidative phosphorylation that supports this stability are poorly understood. We tested the hypotheses that (1) there is parallel activation of mitochondrial and cytosolic dehydrogenases in the transition from low to high workload, which increases NADH/NAD+ ratio in both compartments, and (2) this response does not require an increase in fatty acid oxidation (FAO). Anaesthetized pigs were subjected to either sham treatment, or an abrupt increase in cardiac workload for 5 min with dobutamine infusion and aortic constriction. Myocardial oxygen consumption and FAO were increased 3- and 2-fold, respectively, but ATP and ADP concentrations did not change. NADH-generating pathways were rapidly activated in both the cytosol and mitochondria, as seen in a 40% depletion in glycogen stores, a 3.6-fold activation of pyruvate dehydrogenase, and a 50% increase in tissue NADH/NAD+. Simulations from a multicompartmental computational model of cardiac energy metabolism predicted that parallel activation of glycolysis and mitochondrial metabolism results in an increase in the NADH/NAD+ ratio in both cytosol and mitochondria. FAO was blocked by 75% in a third group of pigs, and a similar increase in and the NAHD/NAD+ ratio was observed. In conclusion, in the transition to a high cardiac workload there is rapid parallel activation of substrate oxidation that results in an increase in the NADH/NAD+ ratio.
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Lufang
authors.initials: L
authors.lastname: Zhou
authors.forename: Marco E
authors.initials: ME
authors.lastname: Cabrera
authors.forename: Hazel
authors.initials: H
authors.lastname: Huang
authors.forename: Celvie L
authors.initials: CL
authors.lastname: Yuan
authors.forename: Duda K
authors.initials: DK
authors.lastname: Monika
authors.forename: Naveen
authors.initials: N
authors.lastname: Sharma
authors.forename: Fang
authors.initials: F
authors.lastname: Bian
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001011:Aorta; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology; D003198:Computer Simulation; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D004280:Dobutamine / Q000494:pharmacology; D004734:Energy Metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D019344:Lactic Acid / Q000378:metabolism; D008026:Ligation; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology*; D034421:Sus scrofa; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology
chemical_list: D001786:Blood Glucose; D002316:Cardiotonic Agents; D005227:Fatty Acids; D009243:NAD; D019344:Lactic Acid; D004280:Dobutamine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate