title: Sarcomere lattice geometry influences cooperative myosin binding in muscle.
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 Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, Washington, USA.
authors.forename: Bertrand C W
authors.initials: BC
authors.lastname: Tanner
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Daniel
authors.forename: Michael
authors.initials: M
authors.lastname: Regnier
mesh_terms: D000199:Actins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D020013:Calcium Signaling; D003198:Computer Simulation; D004548:Elasticity; D004735:Energy Transfer / Q000502:physiology; D007700:Kinetics; D008954:Models, Biological; D009010:Monte Carlo Method; D009068:Movement / Q000502:physiology; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D009119:Muscle Contraction; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D009218:Myosins / Q000378:metabolism*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012518:Sarcomeres / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D014335:Tropomyosin / Q000378:metabolism; D014336:Troponin / Q000378:metabolism
chemical_list: D000199:Actins; D046912:Multiprotein Complexes; D014335:Tropomyosin; D014336:Troponin; D000255:Adenosine Triphosphate; D009218:Myosins