TY - JOUR
T1 - Remodeling of substrate consumption in the murine sTAC model of heart failure
AU - Turer, A.
AU - Altamirano, Francisco
AU - Schiattarella, Gabriele G.
AU - May, Herman
AU - Gillette, Thomas G.
AU - Malloy, Craig R.
AU - Merritt, Matthew E.
N1 - Funding Information:
CM was supported by NIH grant P41-EB015908 . MM was supported by NIH - DK105346 , HD087306 , DK112865 , P41122698 , U24DK097209 , R37-HL034557 , and NSF DMR 1644779. The sponsors did not contribute to the study design. AT, FA, GS, and TG were supported by NIH - HL120732 , HL126012 , and HL128215 . AT, FA, GS, and TG were also supported by American Heart Association grants 14SFRN20510023 and 14SFRN20670003 .
Funding Information:
CM was supported by NIH grant P41-EB015908. MM was supported by NIH -DK105346, HD087306, DK112865, P41122698, U24DK097209, R37-HL034557, and NSF DMR 1644779. The sponsors did not contribute to the study design. AT, FA, GS, and TG were supported by NIH-HL120732, HL126012, and HL128215. AT, FA, GS, and TG were also supported by American Heart Association grants 14SFRN20510023 and 14SFRN20670003. MEM would like to thank Dr. Shawn Burgess for many helpful discussions regarding intermediary metabolism.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
KW - Anaplerosis
KW - Fatty acids
KW - Glucose
KW - Ketones
KW - Substrate selection
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U2 - 10.1016/j.yjmcc.2019.07.007
DO - 10.1016/j.yjmcc.2019.07.007
M3 - Article
C2 - 31340162
AN - SCOPUS:85069676266
SN - 0022-2828
VL - 134
SP - 144
EP - 153
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -