Modulation of Fast Transients by Compliance of Crossbridges and Myofilaments

Abstract

Understanding the coupling between actomyosin cycle and compliance of crossbridges and the myofilaments in the 3D sarcomere lattice is essential for interpretation of fast transient data and for extracting key parameters from the observations. This mechano-chemical coupling is complex due to the three-dimensional nature of myosin binding to actin, as well as its effect on the strain-dependence of transition rates between actin-myosin states. In order to assess the effect of crossbridge compliance and myofilament elasticity on sarcomere contraction we implemented both linear and nonlinear crossbridge compliance in the computational platform MUSICO (MUscle SImulation COde). In the model simulation we included nine state myosin cycle (Smith et al., Ann. Biomed. Eng.36(10):1624-40, 2008), up to 20 sarcomeres in series and at least 500 myosin filaments per sarcomere. Stochastic binding in the 3D sarcomere lattice generates large variation of strains in time at any location along the filaments and up to 20% between the filaments. Overall the model predictions are modulated by nonuniform distributions of crossbridge strains along the filament overlap and by variation of forces between the filaments due to the stochastic myosin binding process. The predicted T1-T2 transient responses of the multi-sarcomere system strongly depend on the number of attached crossbridges. This dependence is strongly evident in traces of T1 vs. the imposed length change, y, and to a much lesser degree of the T2-y responses. After matching the observed value of isometric tension before release, the simulations closely recapitulate the rapid tension recovery, after the rapid drop in tension to T1, to the early plateau, T2,followed by a slow tension redevelopment phase to isometric tension. The predicted rates, r, of quick recovery phase following the length step, were similar to observations. However, to obtain good fits to the observed T1-y nonlinear relationship required inclusion nonlinear crossbridge compliance (Kaya et al., Science 329:686-688, 2010). In summary, the precise coupling between nonlinear strain dependent transition rates of the actomyosin cycle, nonlinear crossbridge compliance and elasticity of myofilaments provides excellent quantitative description of the molecular interactions and muscle fiber transient responses.Supported by: R01 AR048776, HD048895 and W.Trust 085309