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J. Biol. Chem., Vol. 283, Issue 52, 36321-36327, December 26, 2008

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Glycolytic Oscillations in Isolated Rabbit Ventricular Myocytes^*

From the Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095

Previous studies have shown that glycolysis can oscillate periodically, driven by feedback loops in regulation of key glycolytic enzymes by free ADP and other metabolites. Here we show both theoretically and experimentally in cardiac myocytes that when the capacity of oxidative phosphorylation and the creatine kinase system to buffer the cellular ATP/ADP ratio is suppressed, glycolysis can cause large scale periodic oscillations in cellular ATP levels (0.02–0.067 Hz), monitored from glibenclamide-sensitive changes in action potential duration or intracellular free Mg²⁺. Action potential duration oscillations originate primarily from glycolysis, since they 1) occur in the presence of cyanide or rotenone, 2) are suppressed by iodoacetate, 3) are accompanied by at most very small mitochondrial membrane potential oscillations, and 4) exhibit an anti-phase relationship to NADH fluorescence. By uncoupling energy supply-demand balance, glycolytic oscillations may promote injury and electrophysiological heterogeneity during acute metabolic stresses, such as acute myocardial ischemia in which both oxidative phosphorylation and creatine kinase activity are inhibited.

Received for publication, June 24, 2008 , and in revised form, October 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health, NHLBI, Grants P01 HL-080111 and R01 HL-071870. This work was also supported by the Laubisch and Kawata Endowments. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. S1 and S2 and Tables S1 and S2.

¹ Both of these authors contributed equally to this work.

² To whom correspondence should be addressed: David Geffen School of Medicine at UCLA, 675 Charles Young Dr. S., 3645 MRL, Los Angeles, CA 90095-1760. Tel.: 310-825-9029; Fax: 310-206-5777; E-mail: zqu{at}mednet.ucla.edu.

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