The Mathematical Institute, University of Oxford, Eprints Archive

A metabolite-sensitive, thermodynamically-constrained model of
cardiac cross-bridge cycling: Implications for force development during ischemia

Tran, Kenneth and Smith, Nic and Loiselle, Denis and Crampin, E. J. (2009) A metabolite-sensitive, thermodynamically-constrained model of
cardiac cross-bridge cycling: Implications for force development during ischemia.
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Abstract

We present a metabolically regulated model of cardiac active force generation with which we investigate the effects of ischemia on maximum forceproduction. Our model, based on the Rice et al. (2008) model of cross-bridge kinetics, reproduces many of the observed effects of MgATP, MgADP, Pi and H+ on force development while still retaining the force/length/Ca2+ properties of the original model. We introduce three new parameters to account for the competitive binding of H+ to the Ca2+ 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.

Item Type:Article
Subjects:D - G > General
Research Groups:Oxford Centre for Collaborative Applied Mathematics
ID Code:855
Deposited By:Kate Lewin
Deposited On:01 Dec 2009 08:47
Last Modified:01 Dec 2009 08:47

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