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

Kenneth Tran, Nicolas P. Smith, Denis S. Loiselle, Edmund J. Crampin

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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.
Original languageEnglish (US)
Pages (from-to)267-276
Number of pages10
JournalBiophysical Journal
Issue number2
StatePublished - Jan 2010
Externally publishedYes

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledged KAUST grant number(s): KUK-C1-013-04
Acknowledgements: 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.
This publication acknowledges KAUST support, but has no KAUST affiliated authors.


Dive into the research topics of 'A Metabolite-Sensitive, Thermodynamically Constrained Model of Cardiac Cross-Bridge Cycling: Implications for Force Development during Ischemia'. Together they form a unique fingerprint.

Cite this