Abstract
In muscle, force emerges from myosin binding with actin (forming a cross-bridge). This actomyosin binding depends upon myofilament geometry, kinetics of thin-filament Ca2+ activation, and kinetics of cross-bridge cycling. Binding occurs within a compliant network of protein filaments where there is mechanical coupling between myosins along the thick-filament backbone and between actin monomers along the thin filament. Such mechanical coupling precludes using ordinary differential equation models when examining the effects of lattice geometry, kinetics, or compliance on force production. This study uses two stochastically driven, spatially explicit models to predict levels of cross-bridge binding, force, thin-filament Ca2+ activation, and ATP utilization. One model incorporates the 2-to-1 ratio of thin to thick filaments of vertebrate striated muscle (multi-filament model), while the other comprises only one thick and one thin filament (two-filament model). Simulations comparing these models show that the multi-filament predictions of force, fractional cross-bridge binding, and cross-bridge turnover are more consistent with published experimental values. Furthermore, the values predicted by the multi-filament model are greater than those values predicted by the two-filament model. These increases are larger than the relative increase of potential inter-filament interactions in the multi-filament model versus the two-filament model. This amplification of coordinated cross-bridge binding and cycling indicates a mechanism of cooperativity that depends on sarcomere lattice geometry, specifically the ratio and arrangement of myofilaments.
Highlights
Muscle contraction is initiated by Ca2þ binding to troponin and the subsequent movement of tropomyosin on the thin filament, enabling myosin to cyclically attach and detach to actin [1,2,3,4,5,6,7]
Considerable evidence shows that Ca2þ and cross-bridge binding at one location in the sarcomere can influence these processes at proximal regions of the sarcomere, implying that coupled kinetics of thin-filament activation and cross-bridge cycling determine the level of force generated in striated muscle
Three principle conclusions follow from our analysis of the multi-filament and two-filament models: 1) the multi-filament model simulates literature values of skeletal muscle force, ATPase, and cross-bridge binding better than the twofilament model; 2) in the absence of a cross-bridge feedback on thin-filament activation, there is no difference in Ca2þ sensitivity between the two models; and 3) multi-filament model geometry amplifies the influence of filament compliance on cross-bridge binding and turnover
Summary
Muscle contraction is initiated by Ca2þ binding to troponin and the subsequent movement of tropomyosin on the thin filament, enabling myosin to cyclically attach and detach to actin (cross-bridge cycling) [1,2,3,4,5,6,7] Underlying this process are myriad factors that contribute to the magnitude and time course of force production. These factors include the geometry of filaments in the sarcomere, the mechanical properties of the filaments and cross-bridges, the kinetics of thin-filament activation by Ca2þ, and the kinetics of crossbridge cycling. Considerable evidence shows that Ca2þ and cross-bridge binding at one location in the sarcomere can influence these processes at proximal regions of the sarcomere (reviewed in [7]), implying that coupled kinetics of thin-filament activation and cross-bridge cycling determine the level of force generated in striated muscle
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