Effect of Nonlinear Crossbridge Elasticity on Kinetics of Sarcomeric Contraction

Abstract

Coupling between the biochemical cycle and sarcomere mechanics is dictated by the strain dependence of the actomyosin cycle, which is dependent upon crossbridge compliance. Mechano-chemical coupling is even more complex in the sarcomere lattice due to the three-dimensional nature of myosin binding to actin, as well as its effect on strain-dependence of transition rates between actin-myosin states. Recent measurements of nonlinear crossbridge compliance (Kaya et al., Science 329:686-688) and our theoretical investigation demonstrated that energy landscapes are asymmetric because the crossbridges are much more compliant in compression than in tension due to a combination of buckling and bending of S2. Thus, actin-myosin transition rates are also significantly altered too. In order to assess the effect of nonlinear crossbridge compliance on sarcomere contraction we implemented the observed nonlinear crossbridge compliance in the computational platform MUSICO(MUscle SImulation COde). In addition, this platform includes explicit 3-D sarcomere structure, extensible actin and myosin filaments, various models for the actomyosin cycles and the thin filament regulation via continuous flexible chain (CFC). We compared the model predictions between linear and nonlinear crossbridge compliances for classical experiments in muscle, such as force development, isotonic shortening or lengthening and T1-T2 transitions. The predictions from the nonlinear crossbridge sarcomeric model deviated largely from the observations. The main problems are the small resistance of compressed crossbridges during shortening and distorted profile power stroke transition rates. Simple adjustments of actin-myosin transition rates provided some improvements but the model predictions are still far from the observations. Thus, these findings invite re-examination of models of muscle contraction and revision of basic understanding of actomyosin cycle in the 3-D sarcomere lattice.Supported by: NIH R01 AR048776 and R01 DC 011528, and Serbian Ministry of Science grants III41007 and OI174028.