Abstract
Muscle contraction results from cyclic interactions between myosin II motors and actin with two sets of proteins organized in overlapping thick and thin filaments, respectively, in a nearly crystalline lattice in a muscle sarcomere. However, a sarcomere contains a huge number of other proteins, some with important roles in muscle contraction. In particular, these include thin filament proteins, troponin and tropomyosin; thick filament proteins, myosin binding protein C; and the elastic protein, titin, that connects the thin and thick filaments. Furthermore, the order and 3D organization of the myofilament lattice may be important per se for contractile function. It is possible to model muscle contraction based on actin and myosin alone with properties derived in studies using single molecules and biochemical solution kinetics. It is also possible to reproduce several features of muscle contraction in experiments using only isolated actin and myosin, arguing against the importance of order and accessory proteins. Therefore, in this paper, it is hypothesized that “single molecule actomyosin properties account for the contractile properties of a half sarcomere during shortening and isometric contraction at almost saturating Ca concentrations”. In this paper, existing evidence for and against this hypothesis is reviewed and new modeling results to support the arguments are presented. Finally, further experimental tests are proposed, which if they corroborate, at least approximately, the hypothesis, should significantly benefit future effective analysis of a range of experimental studies, as well as drug discovery efforts.
Highlights
Contraction of striated muscle is the result of ATP driven interactions between the contractile proteins actin and myosin II (Figure 1) [1,2]
Despite the apparent complexity and added functions of a muscle sarcomere as compared with isolated actin and myosin, recent modeling work [23,29,30,31,32] has successfully accounted for the contractile properties of muscle, for example, the force-velocity (FV) relationship (Figure 2)
The statement that there should be no effect of 3D order requires some clarification. This means that the order does not alter the actin–myosin interaction in a half sarcomere per se
Summary
Contraction of striated muscle (heart and skeletal muscle) is the result of ATP driven interactions between the contractile proteins actin and myosin II (Figure 1) [1,2]. Despite the apparent complexity and added functions of a muscle sarcomere as compared with isolated actin and myosin, recent modeling work [23,29,30,31,32] has successfully accounted for the contractile properties of muscle, for example, the force-velocity (FV) relationship (Figure 2). The bottom-up models, without adjustments of the preset parameter values more than within experimental uncertainties to fit the data, have been successful in accounting for the rate of increase in isometric force, at least for the upper 50% of the rising phase, for the steady-state FV relationship for shortening, and for several other features such as the relationship between sliding velocity and [MgATP] [29,31,32] This was achieved without invoking effects of 3D order, accessory proteins (titin, troponin/tropomyosin, myosin-binding protein C), or emergent cooperative phenomena. The parameters x1 , x11 , and x2 , indicated in the figure, denote the x-values where the free energy of the states AMDPPP , AMDPPiR (as well as AMDL ), and AMDH , respectively, attain their minimum value
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