Tuning Cooperativity of Calcium Activation in Cardiac Muscle
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Early phase diastole and diastolic performance (filling) via resting ventricular wall tension can be affected by abnormalities in relaxation. This is one of the rarely studied effects of mutations in cardiac muscle sarcomere proteins, which are usually assessed using the force-pCa relations of demembranated muscle or transient twitch contractions in intact muscles. The characteristics of calcium sensitivity (pCa50) and cooperativity (Hill coefficient, nH) may be obtained from force-pCa relations. Using MUSICO simulations, tightly coupled with the experiments, we were able to adjust calcium sensitivity and cooperativity to closely match experimental values by testing the contributions of three mechanisms to contraction and relaxation kinetics: (1) Tm azimuthal movement as a continuous flexible chain (CFC); (2) variations in calcium affinity of cTn; and (3) inclusion of a super-relaxed myosin state (SRX) to reduce the number of myosins that can rebind during relaxation and modulate cooperativity between bound myosin and the CFC.
Simulations provided force-pCa relations where Ca2+ affinity to cTnC was increased or decreased to match the observations in the experiments where native cTnC was replaced with either cTnC L48Q or cTnC I61Q, respectively. Simulations demonstrated that the proposed mechanism, where mutated cTnC changes the dissociation rate of calcium, cannot match experimental pCa50 values for cTnC mutants nor the observed cooperativity (nH). Adjusting the affinity of myosin to actin and the confined persistent length (CPL) of the CFC could account for the apparent loss of cooperativity of thin filament activation for both mutants. However, in WT muscle, the predicted cooperativity was significantly lower than observed. Fine-tuning the calcium dependent transition rate from the SRX, though, allowed a close match to the experimental nH from the force-pCa relations while maintaining CPL values in the physiological range.
KeywordsMUSICO Thin filament regulation Cooperativity Cardiomyopathy cTnC mutations
This project is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 777204. We are also gratefully acknowledging the help of Prof. Thomas C. Irving with editing the final version of the manuscript.
Note: This article reflects only the author’s view. The European Commission is not responsible for any use that may be made of the information it contains.