Since regulation of cardiac muscle contraction is complex, many simulation studies have been conducted to systematically analyze regulatory mechanisms underlying the force-velocity relationship. However, past studies were performed with models lacking detailed thin filament activation despite its essential regulatory role. Here a novel cardiac muscle contraction model is presented that considers troponin C, troponin I and tropomyosin for thin filament activation coupled with the cross-bridge (Xb) cycle, and in addition, includes a potential Frank-Starling mechanism and simple Xb mechanics. This model was employed to elucidate load and sarcomere length-dependence of the thin filament and Xb kinetics during muscle shortening and relaxation. Simulation analysis of afterloaded isotonic contractions performed at various preloads revealed that at medium to high load the peak Xb concentration, regulated by a load-dependent change of the ADP release rate, is the major factor in determining the end-systolic half sarcomere length, whereas the velocitydependent Xb force only shows a small influence. At low load, shortening velocity is regulated through an increase in the rate of the tropomyosin conformational change as for all preloads the same Xb concentration is attained. Shorteninginduced cooperative deactivation was caused by the included Frank-Starling mechanism. An analysis of newly suggested relaxation mechanisms showed the significance for an increased thin filament deactivation with troponin I pulling tropomyosin to the “off” position having a greater impact than titin restoring force assumed to disrupt the tropomyosin structure. A combination of this model with the myocyte Kyoto Model satisfactorily reproduced isotonic contraction time courses from guinea pig myocytes.
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