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/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.

Elucidation of Isoform-dependent pH Sensitivity of Troponin I by NMR Spectroscopy

“…This decrease in contractility occurs despite an elevation of the Ca 2ϩ transient during acidosis (52). Instead, the increase of adenosine diphosphate, inorganic phosphate, and proton concentrations may inhibit actomyosin-ATPase activity (53,54), and the increased [H ϩ ] may decrease Ca 2ϩ sensitivity by lowering the affinity of troponin for Ca 2ϩ (6 -8). Interestingly, slow and fast skeletal muscles are less sensitive to acidic conditions than cardiac muscle (10,12).…”

Dynamics of cross-bridge cycling, ATP hydrolysis, force generation, and deformation in cardiac muscle

“…Previous studies have applied this approach [9–13], however none of these have accounted for the effect of metabolites on the kinetics. Similarly, a previously developed kinetic model [14] that does account for metabolite concentrations (energetic state) on XB cycling does not account for the coupling of deformation/strain and kinetics. One of the goals of the present study is to integrate the phenomena accounted for in these two classes of models to gain an improved understanding of muscle biomechanics and bioenergetics.…”

“…Attempts have been made to quantitatively describe A-, B-, and C-processes of sinusoidal perturbation experiments using empirical expressions [15, 20, 21] or qualitatively describe the elastic and viscous moduli obtained from such experiments [18, 22, 23]. Previous studies have either quantitatively described sinusoidal length perturbation experiments [17], or the effect of metabolites on XB kinetics [14, 24] but not both.…”

The Effect of Bioenergetic Impairment of Cytosolic Processes in Spatio:Temporal Ca2+ Dynamics in a Three:Dimensional Cardiomyocyte Model

“…For this study a previously developed model of spatiotemporal Ca 2+ cycling and electrophysiology was modified to incorporate a model of bioenergetics and force production [5]- [7]. The 3D model was constructed of 20,000 compartments each containing a Ca 2+ release unit (CRU) and associated mitochondria.…”

“…For simulation of the levels of ATP hydrolysis by actomyosin ATPase, the Tran et al model of force production was incorporated [7]. Regulation of force production was linked to the average cytosolic Ca 2+ concentration and the model linked to the bioenergetics model through whole cell average ATP/ADP concentrations.…”