title: Propionate stimulates pyruvate oxidation in the presence of acetate.
abstract: Flux through pyruvate dehydrogenase (PDH) in the heart may be reduced by various forms of injury to the myocardium, or by oxidation of alternative substrates in normal heart tissue. It is important to distinguish these two mechanisms because imaging of flux through PDH based on the appearance of hyperpolarized (HP) [(13)C]bicarbonate derived from HP [1-(13)C]pyruvate has been proposed as a method for identifying viable myocardium. The efficacy of propionate for increasing PDH flux in the setting of PDH inhibition by an alternative substrate was studied using isotopomer analysis paired with exams using HP [1-(13)C]pyruvate. Hearts from C57/bl6 mice were supplied with acetate (2 mM) and glucose (8.25 mM). (13)C NMR spectra were acquired in a cryogenically cooled probe at 14.1 Tesla. After addition of hyperpolarized [1-(13)C]pyruvate, (13)C NMR signals from lactate, alanine, malate, and aspartate were easily detected, in addition to small signals from bicarbonate and CO2. The addition of propionate (2 mM) increased appearance of HP [(13)C]bicarbonate >30-fold without change in O2 consumption. Isotopomer analysis of extracts from the freeze-clamped hearts indicated that acetate was the preferred substrate for energy production, glucose contribution to energy production was minimal, and anaplerosis was stimulated in the presence of propionate. Under conditions where production of acetyl-CoA is dominated by the availability of an alternative substrate, acetate, propionate markedly stimulated PDH flux as detected by the appearance of hyperpolarized [(13)C]bicarbonate from metabolism of hyperpolarized [1-(13)C]pyruvate.
authors.affiliation: School of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Colin
authors.initials: C
authors.lastname: Purmal
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Blanka
authors.initials: B
authors.lastname: Kucejova
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Chemistry, University of Texas at Dallas, Richardson, Texas; and.
authors.forename: A Dean
authors.initials: AD
authors.lastname: Sherry
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Veterans Affairs North Texas Healthcare System, Dallas, Texas.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Malloy
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Chemistry, University of Texas at Dallas, Richardson, Texas; and matthew.merritt@utsouthwestern.edu.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Merritt
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D011422:Propionates / Q000494:pharmacology*; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D000085:Acetates; D001639:Bicarbonates; D011422:Propionates; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D030481:Pyruvate Dehydrogenase (Lipoamide); D005947:Glucose; C029658:propionic acid
keywords: glucose; hyperpolarization; isotopomer analysis; propionate; pyruvate; substrate selection