Mechano-chemical Interactions in Cardiac Sarcomere Contraction: A Computational Modeling Study

Abstract

We developed a model of cardiac sarcomere contraction to study the calcium-tension relationship in cardiac muscle. Calcium mediates cardiac contraction through its interactions with troponin (Tn) and subsequently tropomyosin molecules. Experimental studies have shown that a slight increase in intracellular calcium concentration leads to a rapid increase in sarcomeric tension. Though it is widely accepted that the rapid increase is not possible without the concept of cooperativity, the mechanism is debated. We use the hypothesis that there exists a base level of cooperativity intrinsic to the thin filament that is boosted by mechanical tension, i.e. a high level of mechanical tension in the thin filament impedes the unbinding of calcium from Tn. To test these hypotheses, we developed a computational model in which a set of three parameters and inputs of calcium concentration and sarcomere length result in output tension. Tension as simulated appeared in good agreement with experimentally measured tension. Our results support the hypothesis that high tension in the thin filament impedes Tn deactivation by increasing the energy required to detach calcium from the Tn. Given this hypothesis, the model predicted that the areas with highest tension, i.e. closest to the Z-disk end of the single overlap region, show the largest concentration of active Tn’s.

Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model

“…Later, other authors used similar approaches in their models, for example, Landsberg and Sideman [84], Jeremy Rice [26], and Lauren Dupuis [85,86]. These authors studied the contribution of mechanical conditions of contraction to myocardial mechanical activity and applied their models to assess and analyze in vitro data obtained in experiments on various warm-blooded animal heart muscles.…”

Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model

“…Later, other authors also used similar approaches in the models they develop, for example, in Landsberg and Sideman model [85], Jeremy Rice model [26], Lauren Dupuis model [86,87], in which contribution of mechanical conditions of the contractions to the myocardial mechanical activity was studied and applied to assess and analyze in vitro data obtained in experiments on various warm-blooded animal heart muscles. The contribution of length and/or load to the Ca-TnC kinetics is justified differently in these models and is consequently given by different formulas in the equations describing this kinetics.…”

Mechano-Chemical Interactions in the Isotonic Twitch: A Modeling Study

“…This is only possible in the SOR of the sarcomere, defined as the length of thin filament that overlaps with one thick filament and no other thin filaments. We calculate the length of the SOR as described previously [3].…”

“…Force generation in the cardiac sarcomere is cooperative, meaning that small increases in the intracellular Ca 2+ concentration produce disproportionately large increases in force [2]. We have proposed a novel mechanism of cooperativity in which an intrinsic chemical cooperativity in the thin filament is boosted by mechanical tension [3]. High tension locally along the thin filament impedes the unbinding of Ca 2+ from the Tn, thereby hindering relaxation.…”

“…High tension locally along the thin filament impedes the unbinding of Ca 2+ from the Tn, thereby hindering relaxation. Based on this proposed mechanism of cooperativity, we developed the MechChem model of mechano-chemical interactions in cardiac sarcomere contractions [3] that was validated against experimental data on steady-state isometric contraction in skinned muscle [2] and isometric twitches in myofibers [4,5]. The aim of this study is to extend the MechChem model to mimic isotonic twitch experiments where the sarcomere can contract and shorten against different afterloads.…”