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Sensitivity Analysis of Flux Determination in Heart by H(2) (18)O -provided Labeling Using a Dynamic Isotopologue Model of Energy Transfer Pathways

To characterize intracellular energy transfer in the heart, two organ-level methods have frequently been employed: [Image: see text] inversion and saturation transfer, and dynamic [Image: see text] labeling. Creatine kinase (CK) fluxes obtained by following oxygen labeling have been considerably sma...

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Autores principales: Schryer, David W., Peterson, Pearu, Illaste, Ardo, Vendelin, Marko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516558/
https://www.ncbi.nlm.nih.gov/pubmed/23236266
http://dx.doi.org/10.1371/journal.pcbi.1002795
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author Schryer, David W.
Peterson, Pearu
Illaste, Ardo
Vendelin, Marko
author_facet Schryer, David W.
Peterson, Pearu
Illaste, Ardo
Vendelin, Marko
author_sort Schryer, David W.
collection PubMed
description To characterize intracellular energy transfer in the heart, two organ-level methods have frequently been employed: [Image: see text] inversion and saturation transfer, and dynamic [Image: see text] labeling. Creatine kinase (CK) fluxes obtained by following oxygen labeling have been considerably smaller than the fluxes determined by [Image: see text] saturation transfer. It has been proposed that dynamic [Image: see text] labeling determines net flux through CK shuttle, whereas [Image: see text] saturation transfer measures total unidirectional flux. However, to our knowledge, no sensitivity analysis of flux determination by oxygen labeling has been performed, limiting our ability to compare flux distributions predicted by different methods. Here we analyze oxygen labeling in a physiological heart phosphotransfer network with active CK and adenylate kinase (AdK) shuttles and establish which fluxes determine the labeling state. A mathematical model consisting of a system of ordinary differential equations was composed describing [Image: see text] enrichment in each phosphoryl group and inorganic phosphate. By varying flux distributions in the model and calculating the labeling, we analyzed labeling sensitivity to different fluxes in the heart. We observed that the labeling state is predominantly sensitive to total unidirectional CK and AdK fluxes and not to net fluxes. We conclude that measuring dynamic incorporation of [Image: see text] into the high-energy phosphotransfer network in heart does not permit unambiguous determination of energetic fluxes with a higher magnitude than the ATP synthase rate when the bidirectionality of fluxes is taken into account. Our analysis suggests that the flux distributions obtained using dynamic [Image: see text] labeling, after removing the net flux assumption, are comparable with those from [Image: see text] inversion and saturation transfer.
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spelling pubmed-35165582012-12-12 Sensitivity Analysis of Flux Determination in Heart by H(2) (18)O -provided Labeling Using a Dynamic Isotopologue Model of Energy Transfer Pathways Schryer, David W. Peterson, Pearu Illaste, Ardo Vendelin, Marko PLoS Comput Biol Research Article To characterize intracellular energy transfer in the heart, two organ-level methods have frequently been employed: [Image: see text] inversion and saturation transfer, and dynamic [Image: see text] labeling. Creatine kinase (CK) fluxes obtained by following oxygen labeling have been considerably smaller than the fluxes determined by [Image: see text] saturation transfer. It has been proposed that dynamic [Image: see text] labeling determines net flux through CK shuttle, whereas [Image: see text] saturation transfer measures total unidirectional flux. However, to our knowledge, no sensitivity analysis of flux determination by oxygen labeling has been performed, limiting our ability to compare flux distributions predicted by different methods. Here we analyze oxygen labeling in a physiological heart phosphotransfer network with active CK and adenylate kinase (AdK) shuttles and establish which fluxes determine the labeling state. A mathematical model consisting of a system of ordinary differential equations was composed describing [Image: see text] enrichment in each phosphoryl group and inorganic phosphate. By varying flux distributions in the model and calculating the labeling, we analyzed labeling sensitivity to different fluxes in the heart. We observed that the labeling state is predominantly sensitive to total unidirectional CK and AdK fluxes and not to net fluxes. We conclude that measuring dynamic incorporation of [Image: see text] into the high-energy phosphotransfer network in heart does not permit unambiguous determination of energetic fluxes with a higher magnitude than the ATP synthase rate when the bidirectionality of fluxes is taken into account. Our analysis suggests that the flux distributions obtained using dynamic [Image: see text] labeling, after removing the net flux assumption, are comparable with those from [Image: see text] inversion and saturation transfer. Public Library of Science 2012-12-06 /pmc/articles/PMC3516558/ /pubmed/23236266 http://dx.doi.org/10.1371/journal.pcbi.1002795 Text en © 2012 Schryer et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Schryer, David W.
Peterson, Pearu
Illaste, Ardo
Vendelin, Marko
Sensitivity Analysis of Flux Determination in Heart by H(2) (18)O -provided Labeling Using a Dynamic Isotopologue Model of Energy Transfer Pathways
title Sensitivity Analysis of Flux Determination in Heart by H(2) (18)O -provided Labeling Using a Dynamic Isotopologue Model of Energy Transfer Pathways
title_full Sensitivity Analysis of Flux Determination in Heart by H(2) (18)O -provided Labeling Using a Dynamic Isotopologue Model of Energy Transfer Pathways
title_fullStr Sensitivity Analysis of Flux Determination in Heart by H(2) (18)O -provided Labeling Using a Dynamic Isotopologue Model of Energy Transfer Pathways
title_full_unstemmed Sensitivity Analysis of Flux Determination in Heart by H(2) (18)O -provided Labeling Using a Dynamic Isotopologue Model of Energy Transfer Pathways
title_short Sensitivity Analysis of Flux Determination in Heart by H(2) (18)O -provided Labeling Using a Dynamic Isotopologue Model of Energy Transfer Pathways
title_sort sensitivity analysis of flux determination in heart by h(2) (18)o -provided labeling using a dynamic isotopologue model of energy transfer pathways
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516558/
https://www.ncbi.nlm.nih.gov/pubmed/23236266
http://dx.doi.org/10.1371/journal.pcbi.1002795
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