Glycolysis and pyruvate oxidation in cardiac hypertrophy - Why so unbalanced?

McDonald Research Laboratories/The iCAPTUR4E Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6.
Comparative Biochemistry and Physiology - Part A Molecular & Integrative Physiology (Impact Factor: 1.97). 09/2003; 135(4):499-513. DOI: 10.1016/S1095-6433(03)00007-2
Source: PubMed


Cardiac hypertrophy, induced by chronic pressure or volume overload, is associated with abnormalities in energy metabolism as well as characteristic increases in muscle mass and alterations in the structure of the heart. Hypertrophied hearts display increased rates of glycolysis and overall glucose utilization, but rates of pyruvate oxidation do not rise in step with rates of pyruvate generation. Glycolysis and glucose oxidation, therefore, become markedly less 'coupled' in hypertrophied hearts than in non-hypertrophied hearts. Because the pyruvate dehydrogenase complex (PDC) contributes so powerfully to the control of glucose oxidation, we set out to test the hypothesis that the function of PDC is impaired in cardiac hypertrophy. In this review we describe evidence indicating that the alterations in glucose metabolism in hypertrophied hearts cannot be explained simply by changes in PDC expression or control. Additional mechanisms that may lead to an altered balance of pyruvate metabolism in cardiac hypertrophy are discussed, with commentaries on possible changes in pyruvate transport, NADH shuttles, lactate dehydrogenase, and amino acid metabolism.

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Available from: Roger W Brownsey, Jan 11, 2016
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    • "Specifically, the extent to which glucose passing through glycolysis is catabolized non-oxidatively (i.e, is converted to lactate rather to CO2) appears to be of functional significance, as rates of non-oxidative glycolysis are inversely related to post-ischemic function of male hypertrophied and non-hypertrophied hearts [22]. An acceleration of overall glycolysis combined with a limitation of glucose oxidation [19,23,24] result in increased rates of non-oxidative glycolysis in hypertrophied male hearts [22]. That accelerated rates of non-oxidative glycolysis contribute to the poor outcome of hypertrophied hearts after ischemia is supported by data showing that stimulation of glucose oxidation and/or reduction of glycolysis, effects that alone or in combination reduce non-oxidative glycolysis, substantially improve function of ischemic-reperfused hypertrophied hearts from male rats [19,22]. "
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    ABSTRACT: Gender influences the cardiac response to prolonged increases in workload, with differences at structural, functional, and molecular levels. However, it is unknown if post-ischemic function or metabolism of female hypertrophied hearts differ from male hypertrophied hearts. Thus, we tested the hypothesis that gender influences post-ischemic function of pressure-overload hypertrophied hearts and determined if the effect of gender on post-ischemic outcome could be explained by differences in metabolism, especially the catabolic fate of glucose. Function and metabolism of isolated working hearts from sham-operated and aortic-constricted male and female Sprague-Dawley rats before and after 20 min of no-flow ischemia (N = 17 to 27 per group) were compared. Parallel series of hearts were perfused with Krebs-Henseleit solution containing 5.5 mM [5-3H/U-14C]-glucose, 1.2 mM [1-14C]-palmitate, 0.5 mM [U-14C]-lactate, and 100 mU/L insulin to measure glycolysis and glucose oxidation in one series and oxidation of palmitate and lactate in the second. Statistical analysis was performed using two-way analysis of variance. The sequential rejective Bonferroni procedure was used to correct for multiple comparisons and tests. Female gender negatively influenced post-ischemic function of non-hypertrophied hearts, but did not significantly influence function of hypertrophied hearts after ischemia such that mass-corrected hypertrophied heart function did not differ between genders. Before ischemia, glycolysis was accelerated in hypertrophied hearts, but to a greater extent in males, and did not differ between male and female non-hypertrophied hearts. Glycolysis fell in all groups after ischemia, except in non-hypertrophied female hearts, with the reduction in glycolysis after ischemia being greatest in males. Post-ischemic glycolytic rates were, therefore, similarly accelerated in hypertrophied male and female hearts and higher in female than male non-hypertrophied hearts. Glucose oxidation was lower in female than male hearts and was unaffected by hypertrophy or ischemia. Consequently, non-oxidative catabolism of glucose after ischemia was lowest in male non-hypertrophied hearts and comparably elevated in hypertrophied hearts of both sexes. These differences in non-oxidative glucose catabolism were inversely related to post-ischemic functional recovery. Gender does not significantly influence post-ischemic function of hypertrophied hearts, even though female sex is detrimental to post-ischemic function in non-hypertrophied hearts. Differences in glucose catabolism may contribute to hypertrophy-induced and gender-related differences in post-ischemic function.
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