A Metabolite-Sensitive, Thermodynamically Constrained Model of Cardiac Cross-Bridge Cycling: Implications for Force Development during Ischemia

Handle URI:
http://hdl.handle.net/10754/597303
Title:
A Metabolite-Sensitive, Thermodynamically Constrained Model of Cardiac Cross-Bridge Cycling: Implications for Force Development during Ischemia
Authors:
Tran, Kenneth; Smith, Nicolas P.; Loiselle, Denis S.; Crampin, Edmund J.
Abstract:
We present a metabolically regulated model of cardiac active force generation with which we investigate the effects of ischemia on maximum force production. Our model, based on a model of cross-bridge kinetics that was developed by others, reproduces many of the observed effects of MgATP, MgADP, Pi, and H(+) on force development while retaining the force/length/Ca(2+) properties of the original model. We introduce three new parameters to account for the competitive binding of H(+) to the Ca(2+) binding site on troponin C and the binding of MgADP within the cross-bridge cycle. These parameters, along with the Pi and H(+) regulatory steps within the cross-bridge cycle, were constrained using data from the literature and validated using a range of metabolic and sinusoidal length perturbation protocols. The placement of the MgADP binding step between two strongly-bound and force-generating states leads to the emergence of an unexpected effect on the force-MgADP curve, where the trend of the relationship (positive or negative) depends on the concentrations of the other metabolites and [H(+)]. The model is used to investigate the sensitivity of maximum force production to changes in metabolite concentrations during the development of ischemia.
Citation:
Tran K, Smith NP, Loiselle DS, Crampin EJ (2010) A Metabolite-Sensitive, Thermodynamically Constrained Model of Cardiac Cross-Bridge Cycling: Implications for Force Development during Ischemia. Biophysical Journal 98: 267–276. Available: http://dx.doi.org/10.1016/j.bpj.2009.10.011.
Publisher:
Elsevier BV
Journal:
Biophysical Journal
KAUST Grant Number:
KUK-C1-013-04
Issue Date:
Jan-2010
DOI:
10.1016/j.bpj.2009.10.011
PubMed ID:
20338848
PubMed Central ID:
PMC2808479
Type:
Article
ISSN:
0006-3495
Sponsors:
The authors thank John Jeremy Rice for helpful discussions during the preparation of this manuscript.This work was supported by a Top Achiever Doctoral Scholarship from the Tertiary Education Commission, New Zealand (to K.T).; Royal Society of New Zealand, Marsden Fund No. 06-UoA-123 (to D.S.L. and N.P.S.); National Institute of Biomedical Imaging and Bioengineering grant No. EB-005825 (to E.J.C. and N.P.S.); and Engineering and Physical Sciences Research Council grant No. EP/G007521 (to N.P.S.). This publication is based on work (by E.J.C.) that was supported in part by award No. KUK-C1-013-04, made by King Abdullah University of Science and Technology.
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Full metadata record

DC FieldValue Language
dc.contributor.authorTran, Kennethen
dc.contributor.authorSmith, Nicolas P.en
dc.contributor.authorLoiselle, Denis S.en
dc.contributor.authorCrampin, Edmund J.en
dc.date.accessioned2016-02-25T12:30:14Zen
dc.date.available2016-02-25T12:30:14Zen
dc.date.issued2010-01en
dc.identifier.citationTran K, Smith NP, Loiselle DS, Crampin EJ (2010) A Metabolite-Sensitive, Thermodynamically Constrained Model of Cardiac Cross-Bridge Cycling: Implications for Force Development during Ischemia. Biophysical Journal 98: 267–276. Available: http://dx.doi.org/10.1016/j.bpj.2009.10.011.en
dc.identifier.issn0006-3495en
dc.identifier.pmid20338848en
dc.identifier.doi10.1016/j.bpj.2009.10.011en
dc.identifier.urihttp://hdl.handle.net/10754/597303en
dc.description.abstractWe present a metabolically regulated model of cardiac active force generation with which we investigate the effects of ischemia on maximum force production. Our model, based on a model of cross-bridge kinetics that was developed by others, reproduces many of the observed effects of MgATP, MgADP, Pi, and H(+) on force development while retaining the force/length/Ca(2+) properties of the original model. We introduce three new parameters to account for the competitive binding of H(+) to the Ca(2+) binding site on troponin C and the binding of MgADP within the cross-bridge cycle. These parameters, along with the Pi and H(+) regulatory steps within the cross-bridge cycle, were constrained using data from the literature and validated using a range of metabolic and sinusoidal length perturbation protocols. The placement of the MgADP binding step between two strongly-bound and force-generating states leads to the emergence of an unexpected effect on the force-MgADP curve, where the trend of the relationship (positive or negative) depends on the concentrations of the other metabolites and [H(+)]. The model is used to investigate the sensitivity of maximum force production to changes in metabolite concentrations during the development of ischemia.en
dc.description.sponsorshipThe authors thank John Jeremy Rice for helpful discussions during the preparation of this manuscript.This work was supported by a Top Achiever Doctoral Scholarship from the Tertiary Education Commission, New Zealand (to K.T).; Royal Society of New Zealand, Marsden Fund No. 06-UoA-123 (to D.S.L. and N.P.S.); National Institute of Biomedical Imaging and Bioengineering grant No. EB-005825 (to E.J.C. and N.P.S.); and Engineering and Physical Sciences Research Council grant No. EP/G007521 (to N.P.S.). This publication is based on work (by E.J.C.) that was supported in part by award No. KUK-C1-013-04, made by King Abdullah University of Science and Technology.en
dc.publisherElsevier BVen
dc.subject.meshModels, Cardiovascularen
dc.titleA Metabolite-Sensitive, Thermodynamically Constrained Model of Cardiac Cross-Bridge Cycling: Implications for Force Development during Ischemiaen
dc.typeArticleen
dc.identifier.journalBiophysical Journalen
dc.identifier.pmcidPMC2808479en
dc.contributor.institutionUniversity of Auckland, Auckland, New Zealanden
dc.contributor.institutionUniversity of Oxford, Oxford, United Kingdomen
kaust.grant.numberKUK-C1-013-04en
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