title: Pyruvate modifies metabolic flux and nutrient sensing during extracorporeal membrane oxygenation in an immature swine model.
abstract: Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support for infants and children with postoperative cardiopulmonary failure. Nutritional support is mandatory during ECMO although specific actions for substrates on the heart have not been delineated. Prior work shows that enhancing pyruvate oxidation promotes successful weaning from ECMO. Accordingly, we tested the hypothesis that prolonged systemic pyruvate supplementation activates pyruvate oxidation in an immature swine model in vivo. Twelve male mixed-breed Yorkshire piglets (age 30-49 days) received systemic infusion of either normal saline (group C) or pyruvate (group P) during the final 6 h of 8 h of ECMO. Over the final hour, piglets received [2-(13)C] pyruvate, as a reference substrate for oxidation, and [(13)C6]-l-leucine, as an indicator for amino acid oxidation and protein synthesis. A significant increase in lactate and pyruvate concentrations occurred, along with an increase in the absolute concentration of the citric acid cycle intermediates. An increase in anaplerotic flux through pyruvate carboxylation in group P occurred compared with no change in pyruvate oxidation. Additionally, pyruvate promoted an increase in the phosphorylation state of several nutrient-sensitive enzymes, like AMP-activated protein kinase and acetyl CoA carboxylase, suggesting activation for fatty acid oxidation. Pyruvate also promoted O-GlcNAcylation through the hexosamine biosynthetic pathway. In conclusion, although prolonged pyruvate supplementation did not alter pyruvate oxidation, it did elicit changes in nutrient- and energy-sensitive pathways. Therefore, the observed results support the further study of pyruvate and its downstream effect on cardiac function.
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington;
authors.forename: Dolena R
authors.initials: DR
authors.lastname: Ledee
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington;
authors.forename: Masaki
authors.initials: M
authors.lastname: Kajimoto
authors.affiliation: Department of Surgery, University of Washington, Seattle, Washington;
authors.forename: Colleen M
authors.initials: CM
authors.lastname: O'Kelly Priddy
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington; Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Olson
authors.affiliation: Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington;
authors.forename: Nancy
authors.initials: N
authors.lastname: Isern
authors.affiliation: Department of Nutrition, Université de Montréal and Montréal Heart Institute, Montréal, Quebec, Canada;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Robillard-Frayne
authors.affiliation: Department of Nutrition, Université de Montréal and Montréal Heart Institute, Montréal, Quebec, Canada;
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington; Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, Washington michael.portman@seattlechildrens.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Portman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000187:drug effects / Q000378:metabolism; D000596:Amino Acids / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D004734:Energy Metabolism / Q000187:drug effects*; D015199:Extracorporeal Membrane Oxygenation; D005227:Fatty Acids / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007930:Leucine / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D066244:Proton Magnetic Resonance Spectroscopy; D019289:Pyruvic Acid / Q000494:pharmacology*; D013552:Swine
chemical_list: D000596:Amino Acids; D002250:Carbon Radioisotopes; D005227:Fatty Acids; D019289:Pyruvic Acid; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D007930:Leucine
keywords: extracorporeal membrane oxygenation; leucine; metabolism; pyruvate