Comparison of putative cooperative mechanisms in cardiac muscle: length dependence and dynamic responses

Length-dependent steady-state and dynamic responses of five models of isome tric force generation in cardiac myofilaments were compared with similar ex perimental data from the literature. The models were constructed by assumin g different subsets of three putative cooperative mechanisms. Cooperative m echanism 1 holds that cross-bridge binding increases the affinity of tropon in for Ca2+. In the models, cooperative mechanism 1 can produce steep force -Ca2+ (F-ca) relations, but apparent cooperativity is highest at midlevel C a2+ concentrations. During twitches, cooperative mechanism 1 has the effect of increasing latency to peak as the magnitude of force increases, an effe ct not seen, experimentally. Cooperative mechanism 2 holds that the binding of a cross bridge increases the rate of formation of neighboring cross bri dges and that multiple cross bridges can maintain activation of the thin fi lament in the absence of Ca2+. Only cooperative mechanism 2 can produce sar comere length (SL)dependent prolongation of twitches, but this mechanism ha s little effect on steady-state F-Ca relations. Cooperativity mechanism 3 i s designed to simulate end-to-end interactions between adjacent troponin an d tropomyosin. This mechanism can produce steep F-Ca relations with appropr iate SL-dependent changes in Ca2+ sensitivity. With the assumption that tro pomyosin shifting is faster than cross-bridge cycling, cooperative mechanis m 3 produces twitches where latency to peak is independent of the magnitude of force, as seen experimentally.