Cooperative effects due to calcium binding by troponin and their consequences for contraction and relaxation of cardiac muscle under various conditions of mechanical loading.

Abstract

A mathematical model for the regulation of mechanical activity in cardiac muscle has been developed based on a three-element rheological model of this muscle. The contractile element has been modeled taking into account the results of extensive mechanical tests that involved the recording of length-force and force-velocity relations and muscle responses to short-time deformations during various phases of the contraction-relaxation cycle. The best agreement between the experimental and the mathematical modeling results was obtained when a postulate stating two types of cooperativity to regulate the calcium binding by troponin was introduced into the model. Cooperativity of the first type is due to the dependence of the affinity of troponin C for Ca2+ on the concentration of myosin crossbridges in the vicinity of a given troponin C. Cooperativity of the second type assumes an increase in the affinity of a given troponin C for Ca2+ when the latter is bound by molecules neighboring troponin.

Функциональная Неднородность Возникающая В Результате Электрического И Механического Взаимодействия Между Кардиомиоцитами В Математической Модели Однородного Волокна

“…6,A, B) [3]. This effect was earlier validated in our cellular model [5,7] incorporated now in the fiber model. The fiber model also proved to simulate this phenomenon correctly:…”

“…Cooperative mechanisms of CaTnC kinetics as well as respective equations are identified and justified in our previous papers [5,8,24]. Thus, direct links and feedback between Ca 2+ kinetics, CEx deformations, and force generation are defined in the EO model and ensured from the cooperative mechanisms of myofilament Ca 2+ activation.…”

“…This occurs along with calcium binding to the regulatory protein troponin C (CaTnC complexes). Detailed interactions between these molecular processes are described in our previous papers [5,9].…”

Load dependence of ventricular performance explained by model of calcium-myofilament interactions

“…It is not necessary to introduce length-dependent myofilament calcium affinity for the four-state model to explain contractile behavior on ejecting beats. Prior investigators advanced the concept of explaining whole heart behavior on the basis of the fundamental principles of muscle contraction (10,11,17,26). The present study represents another step toward this goal by offering a comprehensive explanation for load dependence of ventricular performance, thus advancing understanding of the physiology of the intact heart under physiological conditions.…”

“…Prior theoretical studies have shown that one or another model could in general explain contractile behavior during shortening (17,22), but there has been no prior attempt to explicitly test those models against measured data. The breadth of phenomena explained by the present model, however, should be acknowledged.…”