Tuning Cooperativity of Calcium Activation in Cardiac Muscle

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.