Key result
The MechChem computational model accurately reproduced experimental calcium-tension relationships, supporting the hypothesis that mechanical tension in the thin filament impedes troponin deactivation.
A novel computational model supports the hypothesis that mechanical tension in the cardiac thin filament impedes calcium detachment from troponin, explaining cooperative activation.
Hypothesis-generating for thin filament cooperativity; leaves open translation to human disease or therapy.
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.
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Dupuis et al. (2016) studied Cardiac sarcomere contraction. MechChem computational model vs. Hill-type model was evaluated on Calcium-tension relationship (Root Mean Squared Error). The MechChem computational model accurately reproduced experimental calcium-tension relationships, supporting the hypothesis that mechanical tension in the thin filament impedes troponin deactivation.
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