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

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/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.