Sarcomere Lattice Geometry Influences Cooperative Myosin Binding in Muscle

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.: Striated muscle is highly structured, and the molecular organization of muscle filaments varies within individuals (by fiber type) and taxonomically. The consequences of filament arrangement on muscle contraction, however, remain largely unknown. We explore how filament arrangement affects force production in muscle using spatially explicit models of many interacting myofilaments. Our analysis incorporates molecular scale force balance equations with Monte Carlo simulations of both actin–myosin interactions and thin-filament Ca2+ activation. Simulations show that a more physiological representation of vertebrate striated muscle amplifies force production, coordinates dynamic actin–myosin cycling, and may optimize energetics of contraction (force generated per ATP consumed). This coordinated myosin behavior indicates a mechanism of cooperativity in muscle that depends on the ratio and arrangement of filaments. We also demonstrate the importance of mechanical coupling between myosin molecules by varying filament stiffness. Our simulations show a tradeoff between the way myosin molecules partition energy from ATP hydrolysis into force transmitted throughout the filaments versus distortions within the filaments. These findings present a possible consequence of organization in muscle, where the ratio and arrangement of muscle filaments affects contractile performance for the given function across different muscle types.