R T Mallet1, J Sun. 1. Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth 76107-2699, USA. malletr@hsc.unt.edu
Abstract
UNLABELLED: Pyruvate augmentation of contractile function and cytosolic free energy of ATP hydrolysis in myocardium could result from pyruvate catabolism in the mitochondria or from increased ratio of the cytosolic NAD-/NADH redox couple via the lactate dehydrogenase equilibrium. OBJECTIVE: To test the hypothesis that cytosolic oxidation by pyruvate is sufficient to increase cardiac function and energetics. METHODS: Isolated working guinea-pig hearts received 0.2 mM octanoate +/- 2.5 mM pyruvate as fuels. alpha-Cyano-3-hydroxycinnamate (COHC, 0.6 mM) was administered to selectively inhibit mitochondrial pyruvate uptake without inhibiting pyruvate's cytosolic redox effects or octanoate oxidation. The effects of pyruvate and COHC on sarcoplasmic reticular- Ca2+ handling were examined in 45Ca-loaded hearts. RESULTS: Pyruvate increased left ventricular stroke work and power 40%, mechanical efficiency 29%, and cytosolic ATP phosphorylation potential nearly fourfold. 14CO2 formation from [1-14C]pyruvate was inhibited 65% by COHC, and octanoate oxidation, i.e. 14CO2 formation from [1-14C]octanoate, concomitantly increased threefold. COHC prevented pyruvate enhancement of left ventricular function, mechanical efficiency and cytosolic phosphorylation potential, but did not alter respective levels in pyruvate-free control hearts and augmented cytosolic oxidation by pyruvate. Pyruvate increased sarcoplasmic reticular Ca2+ turnover, i.e. Ca2+ uptake and release, as indicated by 62% decrease in caffeine-induced 45Ca release following 40 min 45Ca washout (P < 0.01). In presence of COHC, pyruvate did not lower caffeine-induced 45Ca release; thus. COHC abrogated pyruvate enhancement of Ca2+ turnover (P < 0.001). CONCLUSION: Pyruvate oxidation of cytosolic redox state is not sufficient to increase cardiac function, cytosolic energetics and sarcoplasmic reticular Ca2+ turnover when mitochondrial pyruvate transport is disabled; thus, mitochondrial metabolism of pyruvate is essential for its metabolic inotropism.
UNLABELLED: Pyruvate augmentation of contractile function and cytosolic free energy of ATP hydrolysis in myocardium could result from pyruvate catabolism in the mitochondria or from increased ratio of the cytosolic NAD-/NADH redox couple via the lactate dehydrogenase equilibrium. OBJECTIVE: To test the hypothesis that cytosolic oxidation by pyruvate is sufficient to increase cardiac function and energetics. METHODS: Isolated working guinea-pig hearts received 0.2 mM octanoate +/- 2.5 mM pyruvate as fuels. alpha-Cyano-3-hydroxycinnamate (COHC, 0.6 mM) was administered to selectively inhibit mitochondrial pyruvate uptake without inhibiting pyruvate's cytosolic redox effects or octanoate oxidation. The effects of pyruvate and COHC on sarcoplasmic reticular- Ca2+ handling were examined in 45Ca-loaded hearts. RESULTS:Pyruvate increased left ventricular stroke work and power 40%, mechanical efficiency 29%, and cytosolic ATP phosphorylation potential nearly fourfold. 14CO2 formation from [1-14C]pyruvate was inhibited 65% by COHC, and octanoate oxidation, i.e. 14CO2 formation from [1-14C]octanoate, concomitantly increased threefold. COHC prevented pyruvate enhancement of left ventricular function, mechanical efficiency and cytosolic phosphorylation potential, but did not alter respective levels in pyruvate-free control hearts and augmented cytosolic oxidation by pyruvate. Pyruvate increased sarcoplasmic reticular Ca2+ turnover, i.e. Ca2+ uptake and release, as indicated by 62% decrease in caffeine-induced 45Ca release following 40 min 45Ca washout (P < 0.01). In presence of COHC, pyruvate did not lower caffeine-induced 45Ca release; thus. COHC abrogated pyruvate enhancement of Ca2+ turnover (P < 0.001). CONCLUSION:Pyruvate oxidation of cytosolic redox state is not sufficient to increase cardiac function, cytosolic energetics and sarcoplasmic reticular Ca2+ turnover when mitochondrial pyruvate transport is disabled; thus, mitochondrial metabolism of pyruvate is essential for its metabolic inotropism.
Authors: Rafael Jaimes; Sarah Kuzmiak-Glancy; Daina M Brooks; Luther M Swift; Nikki G Posnack; Matthew W Kay Journal: Pflugers Arch Date: 2015-07-05 Impact factor: 3.657
Authors: Aaron K Olson; Outi M Hyyti; Gordon A Cohen; Xue-Han Ning; Martin Sadilek; Nancy Isern; Michael A Portman Journal: Am J Physiol Heart Circ Physiol Date: 2008-10-10 Impact factor: 4.733