Published Online
on October 4, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on April 29, 2004
Revised on May 11, 2004

Mechanisms for Increased Glycolysis in the Hypertrophied Rat Heart

Luigino Nascimben^*; Joanne S. Ingwall; Beverly H. Lorell; Ilka Pinz; Vera Schultz; Keith Tornheim; and Rong Tian

From the NMR Laboratory for Physiological Chemistry (L.N., J.S.I., I.P., R.T.), Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School; the Cardiovascular Division (B.H.L.), Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School; and the Department of Biochemistry and the Diabetes and Metabolism Unit (K.T.), Boston University School of Medicine, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: lnascimben{at}partners.org.bwh.harvard.edu.

Abstract--Glycolysis increases in hypertrophied hearts but the mechanisms are unknown. We studied the regulation of glycolysis in hearts with pressure-overload LV hypertrophy (LVH), a model that showed marked increases in the rates of glycolysis (by 2-fold) and insulin-independent glucose uptake (by 3-fold). Although the V_max of the key glycolytic enzymes was unchanged in this model, concentrations of free ADP, free AMP, inorganic phosphate (P_i), and fructose-2,6-bisphosphate (F-2,6-P₂), all activators of the rate-limiting enzyme phosphofructokinase (PFK), were increased (up to 10-fold). Concentrations of the inhibitors of PFK, ATP, citrate, and H⁺ were unaltered in LVH. Thus, our findings show that increased glucose entry and activation of the rate-limiting enzyme PFK both contribute to increased flux through the glycolytic pathway in hypertrophied hearts. Moreover, our results also suggest that these changes can be explained by increased intracellular free [ADP] and [AMP], due to decreased energy reserve in LVH, activating the AMP-activated protein kinase cascade. This, in turn, results in enhanced synthesis of F-2,6-P₂ and increased sarcolemma localization of glucose transporters, leading to coordinated increases in glucose transport and activation of PFK.

Key words: cardiac function • hypertrophy • protein kinases • cardiac metabolism • cyclic AMP

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