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

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.Author Summary: Cardiac contraction is the culmination of multiple subcellular processes beginning with calcium induced activation of the contractile machinery. Interestingly, small increases in intracellular calcium concentrations lead to disproportionately large increases in tension development within the cardiac muscle, a phenomenon known as ‘cooperative activation’. Although the concept of cooperative activation is widely accepted, the mechanism is highly debated. Many complex computational models have been developed in an attempt to understand the underlying mechanisms. However, no single mechanism has been able to properly account for the range of experimental data. We propose that the interaction between the mechanics and chemistry in the contractile unit is an essential component of the cooperative activation. We have developed a simple computational model composed of only five parameters and a single ordinary differential equation that describes the cooperative nature of myocardial contraction through mechanochemical interaction. This model can reproduce experimental data relating to cooperative activation and provides a promising tool for future research.