Aslan Turer1, Francisco Altamirano2, Gabriele G Schiattarella3, Herman May4, Thomas G Gillette5, Craig R Malloy6, Matthew E Merritt7. 1. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, United States of America. Electronic address: Aslan.Turer@UTSouthwestern.edu. 2. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, United States of America. Electronic address: Francisco.Altamirano@utsouthwestern.edu. 3. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, United States of America. Electronic address: Gabriele.Schiattarella@utsouthwestern.edu. 4. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, United States of America. Electronic address: Herman.May@utsouthwestern.edu. 5. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, United States of America. Electronic address: thomas.gillette@utsouthwestern.edu. 6. Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX 75390, United States of America; Department of Radiology, UT Southwestern Medical Center, Dallas, TX 75390, United States of America; VA North Texas Healthcare System, Lancaster, TX, United States of America. Electronic address: craig.malloy@utsouthwestern.edu. 7. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610-0245, United States of America. Electronic address: matthewmerritt@ufl.edu.
Abstract
BACKGROUND: Energy metabolism and substrate selection are key aspects of correct myocardial mechanical function. Myocardial preference for oxidizable substrates changes in both hypertrophy and in overt failure. Previous work has shown that glucose oxidation is upregulated in overpressure hypertrophy, but its fate in overt failure is less clear. Anaplerotic flux of pyruvate into the tricarboxylic acid cycle (TCA) has been posited as a secondary fate of glycolysis, aside from pyruvate oxidation or lactate production. METHODS AND RESULTS: A model of heart failure that emulates both valvular and hypertensive heart disease, the severe transaortic constriction (sTAC) mouse, was assayed for changes in substrate preference using metabolomic and carbon-13 flux measurements. Quantitative measures of O2 consumption in the Langendorff perfused mouse heart were paired with 13C isotopomer analysis to assess TCA cycle turnover. Since the heart accommodates oxidation of all physiological energy sources, the utilization of carbohydrates, fatty acids, and ketones were measured simultaneously using a triple-tracer NMR method. The fractional contribution of glucose to acetyl-CoA production was upregulated in heart failure, while other sources were not significantly different. A model that includes both pyruvate carboxylation and anaplerosis through succinyl-CoA produced superior fits to the data compared to a model using only pyruvate carboxylation. In the sTAC heart, anaplerosis through succinyl-CoA is elevated, while pyruvate carboxylation was not. Metabolomic data showed depleted TCA cycle intermediate pool sizes versus the control, in agreement with previous results. CONCLUSION: In the sTAC heart failure model, the glucose contribution to acetyl-CoA production was significantly higher, with compensatory changes in fatty acid and ketone oxidation not reaching a significant level. Anaplerosis through succinyl-CoA is also upregulated, and is likely used to preserve TCA cycle intermediate pool sizes. The triple tracer method used here is new, and can be used to assess sources of acetyl-CoA production in any oxidative tissue.
BACKGROUND: Energy metabolism and substrate selection are key aspects of correct myocardial mechanical function. Myocardial preference for oxidizable substrates changes in both hypertrophy and in overt failure. Previous work has shown that glucose oxidation is upregulated in overpressure hypertrophy, but its fate in overt failure is less clear. Anaplerotic flux of pyruvate into the tricarboxylic acid cycle (TCA) has been posited as a secondary fate of glycolysis, aside from pyruvate oxidation or lactate production. METHODS AND RESULTS: A model of heart failure that emulates both valvular and hypertensive heart disease, the severe transaortic constriction (sTAC) mouse, was assayed for changes in substrate preference using metabolomic and carbon-13 flux measurements. Quantitative measures of O2 consumption in the Langendorff perfused mouse heart were paired with 13C isotopomer analysis to assess TCA cycle turnover. Since the heart accommodates oxidation of all physiological energy sources, the utilization of carbohydrates, fatty acids, and ketones were measured simultaneously using a triple-tracer NMR method. The fractional contribution of glucose to acetyl-CoA production was upregulated in heart failure, while other sources were not significantly different. A model that includes both pyruvate carboxylation and anaplerosis through succinyl-CoA produced superior fits to the data compared to a model using only pyruvate carboxylation. In the sTAC heart, anaplerosis through succinyl-CoA is elevated, while pyruvate carboxylation was not. Metabolomic data showed depleted TCA cycle intermediate pool sizes versus the control, in agreement with previous results. CONCLUSION: In the sTACheart failure model, the glucose contribution to acetyl-CoA production was significantly higher, with compensatory changes in fatty acid and ketone oxidation not reaching a significant level. Anaplerosis through succinyl-CoA is also upregulated, and is likely used to preserve TCA cycle intermediate pool sizes. The triple tracer method used here is new, and can be used to assess sources of acetyl-CoA production in any oxidative tissue.
Authors: Beverly A Rothermel; Kambeez Berenji; Paul Tannous; William Kutschke; Asim Dey; Bridgid Nolan; Ki-Dong Yoo; Elaine Demetroulis; Michael Gimbel; Barry Cabuay; Mohsen Karimi; Joseph A Hill Journal: Physiol Genomics Date: 2005-07-20 Impact factor: 3.107
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