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      Nonlinear Actomyosin Elasticity in Muscle?

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          Abstract

          Cyclic interactions between myosin II motor domains and actin filaments that are powered by turnover of ATP underlie muscle contraction and have key roles in motility of nonmuscle cells. The elastic characteristics of actin-myosin cross-bridges are central in the force-generating process, and disturbances in these properties may lead to disease. Although the prevailing paradigm is that the cross-bridge elasticity is linear (Hookean), recent single-molecule studies suggest otherwise. Despite convincing evidence for substantial nonlinearity of the cross-bridge elasticity in the single-molecule work, this finding has had limited influence on muscle physiology and physiology of other ordered cellular actin-myosin ensembles. Here, we use a biophysical modeling approach to close the gap between single molecules and physiology. The model is used for analysis of available experimental results in the light of possible nonlinearity of the cross-bridge elasticity. We consider results obtained both under rigor conditions (in the absence of ATP) and during active muscle contraction. Our results suggest that a wide range of experimental findings from mechanical experiments on muscle cells are consistent with nonlinear actin-myosin elasticity similar to that previously found in single molecules. Indeed, the introduction of nonlinear cross-bridge elasticity into the model improves the reproduction of key experimental results and eliminates the need for force dependence of the ATP-induced detachment rate, consistent with observations in other single-molecule studies. The findings have significant implications for the understanding of key features of actin-myosin-based production of force and motion in living cells, particularly in muscle, and for the interpretation of experimental results that rely on stiffness measurements on cells or myofibrils.

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          Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation.

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            Muscle structure and theories of contraction.

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              Skeletal muscle performance determined by modulation of number of myosin motors rather than motor force or stroke size.

              Skeletal muscle can bear a high load at constant length, or shorten rapidly when the load is low. This force-velocity relationship is the primary determinant of muscle performance in vivo. Here we exploited the quasi-crystalline order of myosin II motors in muscle filaments to determine the molecular basis of this relationship by X-ray interference and mechanical measurements on intact single cells. We found that, during muscle shortening at a wide range of velocities, individual myosin motors maintain a force of about 6 pN while pulling an actin filament through a 6 nm stroke, then quickly detach when the motor reaches a critical conformation. Thus we show that the force-velocity relationship is primarily a result of a reduction in the number of motors attached to actin in each filament in proportion to the filament load. These results explain muscle performance and efficiency in terms of the molecular mechanism of the myosin motor.
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                Author and article information

                Contributors
                Journal
                Biophys J
                Biophys. J
                Biophysical Journal
                The Biophysical Society
                0006-3495
                1542-0086
                22 January 2019
                13 December 2018
                : 116
                : 2
                : 330-346
                Affiliations
                [1 ]Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden
                [2 ]Department of Kinesiology and Physical Education, McGill University, Montreal, Canada
                [3 ]Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
                Author notes
                []Corresponding author alf.mansson@ 123456lnu.se
                Article
                S0006-3495(18)34471-0
                10.1016/j.bpj.2018.12.004
                6350078
                30606448
                67df9a11-fb4e-4a3d-a136-477773079b17
                © 2018 Biophysical Society.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 August 2018
                : 5 December 2018
                Categories
                Articles

                Biophysics
                Biophysics

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