The myosin motor in muscle generates a smaller and slower working stroke at higher load

Reconditi, Massimo; Linari, Marco; Lucii, L; Stewart, Alex; Sun, Yin-Biao; Boesecke, Peter; Narayanan, Theyencheri; Fischetti, Robert F.; Irving, Tom; Piazzesi, Gabriella; Irving, Malcolm; Lombardi, Vincenzo

doi:10.1038/nature02380

Cited by 191 publications

(310 citation statements)

References 27 publications

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“…Owing to the dependence of cross-bridge force, duty factor and step size on shortening velocity [64,65], PEVK would increasingly unwind from the thin filaments as the cross-bridge force declines with shortening velocity. In fact, without such unwinding, the amplitude of muscle shortening will be limited unrealistically by the bound PEVK.…”

Section: Titin Winding During Active Shorteningmentioning

confidence: 99%

Is titin a ‘winding filament’? A new twist on muscle contraction

et al. 2011

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Recent studies have demonstrated a role for the elastic protein titin in active muscle, but the mechanisms by which titin plays this role remain to be elucidated. In active muscle, Ca 2þ -binding has been shown to increase titin stiffness, but the observed increase is too small to explain the increased stiffness of parallel elastic elements upon muscle activation. We propose a 'winding filament' mechanism for titin's role in active muscle. First, we hypothesize that Ca 2þ -dependent binding of titin's N2A region to thin filaments increases titin stiffness by preventing low-force straightening of proximal immunoglobulin domains that occurs during passive stretch. This mechanism explains the difference in length dependence of force between skeletal myofibrils and cardiac myocytes. Second, we hypothesize that cross-bridges serve not only as motors that pull thin filaments towards the M-line, but also as rotors that wind titin on the thin filaments, storing elastic potential energy in PEVK during force development and active stretch. Energy stored during force development can be recovered during active shortening. The winding filament hypothesis accounts for force enhancement during stretch and force depression during shortening, and provides testable predictions that will encourage new directions for research on mechanisms of muscle contraction.

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Section: Titin Winding During Active Shorteningmentioning

confidence: 99%

Is titin a ‘winding filament’? A new twist on muscle contraction

et al. 2011

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“…Filament sliding is driven by a change in conformation of the actin-bound myosin head: its working stroke (1)(2)(3). A detailed molecular model for the working stroke has been derived from biochemical and structural studies of isolated myosin head domains and their interaction with actin and ATP (3)(4)(5)(6), and the quasi-crystalline organization of myosin and actin in muscle has allowed this model to be tested and elaborated by mechanical and structural studies on muscle cells (1,2,(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Motion of myosin head domains during activation and force development in skeletal muscle

Reconditi

Brunello²,

Linari³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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114

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Muscle contraction is driven by a change in the structure of the head domain of myosin, the "working stroke" that pulls the actin filaments toward the midpoint of the myosin filaments. This movement of the myosin heads can be measured very precisely in intact muscle cells by X-ray interference, but until now this technique has not been applied to physiological activation and force generation following electrical stimulation of muscle cells. By using this approach, we show that the long axes of the myosin head domains are roughly parallel to the filaments in resting muscle, with their center of mass offset by approximately 7 nm from the C terminus of the head domain. The observed mass distribution matches that seen in electron micrographs of isolated myosin filaments in which the heads are folded back toward the filament midpoint. Following electrical stimulation, the heads move by approximately 10 nm away from the filament midpoint, in the opposite direction to the working stroke. The time course of this motion matches that of force generation, but is slower than the other structural changes in the myosin filaments on activation, including the loss of helical and axial order of the myosin heads and the change in periodicity of the filament backbone. The rate of force development is limited by that of attachment of myosin heads to actin in a conformation that is the same as that during steadystate isometric contraction; force generation in the actin-attached head is fast compared with the attachment step.C ontraction of skeletal muscles is driven by a cyclical interaction between myosin and actin, fueled by the hydrolysis of ATP. The myosin and actin are polymerized into parallel thick and thin filaments, which themselves are organized into a hexagonal array in the muscle cell. The head domains of myosin lie on the surface of the thick filaments and bind to actin in the thin filaments. Filament sliding is driven by a change in conformation of the actin-bound myosin head: its working stroke (1-3). A detailed molecular model for the working stroke has been derived from biochemical and structural studies of isolated myosin head domains and their interaction with actin and ATP (3-6), and the quasi-crystalline organization of myosin and actin in muscle has allowed this model to be tested and elaborated by mechanical and structural studies on muscle cells (1, 2, 7-11).Many of these cell-based studies used rapid perturbations to synchronize the actions of the myosin heads in a muscle cell. Typically, the length of an active muscle fiber was rapidly decreased, displacing each set of myosin filaments by a few nanometers with respect to the opposing actin filaments (2). Such a shortening step produces an elastic force decrease during the step, followed in the next few milliseconds by rapid force regeneration driven by the working stroke in actin-attached myosin heads (2,7,8). This and related protocols have revealed fundamental properties of the working stroke, including its size, speed, and load dependence, and shown how ...

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“…Although the myofibrillar basis of oscillatory work and power production is known (1)(2)(3)(4)(5), the molecular adaptations that allow the indirect flight muscles (IFM) to operate at very high frequencies are less well understood. In muscles of slow-to-moderate speed, muscle velocity is thought to be limited by prolonging the time myosin spends strongly bound to actin before detachment (6,7). The prolongation is essential for coupling enzyme chemical kinetics, which normally occur rapidly, to the slower movements of the sarcomere during normal muscle function.…”

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confidence: 99%

An exceptionally fast actomyosin reaction powers insect flight muscle

Swank

Vishnudas

Maughan

2006

Proc. Natl. Acad. Sci. U.S.A.

115

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Insects, as a group, have been remarkably successful in adapting to a great range of physical and biological environments, in large part because of their ability to fly. The evolution of flight in small insects was accompanied by striking adaptations of the thoracic musculature that enabled very high wing beat frequencies. At the cellular and protein filament level, a stretch activation mechanism evolved that allowed high-oscillatory work to be achieved at very high frequencies as contraction and nerve stimulus became asynchronous. At the molecular level, critical adaptations occurred within the motor protein myosin II, because its elementary interactions with actin set the speed of sarcomere contraction. Here, we show that the key myosin enzymatic adaptations required for powering the very fast flight muscles in the fruit fly Drosophila melanogaster include the highest measured detachment rate of myosin from actin (forward rate constant, 3,698 s ؊1 ), an exceptionally weak affinity of MgATP for myosin (association constant, 0.2 mM ؊1 ), and a unique rate-limiting step in the cross-bridge cycle at the point of inorganic phosphate release. The latter adaptations are constraints imposed by the overriding requirement for exceptionally fast release of the hydrolytic product MgADP. Otherwise, as in Drosophila embryonic muscle and other slow muscle types, a step associated with MgADP release limits muscle contraction speed by delaying the detachment of myosin from actin.cross-bridge cycle ͉ Drosophila ͉ kinetics ͉ myosin I n Drosophila melanogaster two sets of antagonistic, asynchronous flight muscles oscillate at Ϸ200 beats per second, powering the wings indirectly by deforming the thoracic cuticle into which the muscles and wings insert. Although the myofibrillar basis of oscillatory work and power production is known (1-5), the molecular adaptations that allow the indirect flight muscles (IFM) to operate at very high frequencies are less well understood. In muscles of slow-to-moderate speed, muscle velocity is thought to be limited by prolonging the time myosin spends strongly bound to actin before detachment (6, 7). The prolongation is essential for coupling enzyme chemical kinetics, which normally occur rapidly, to the slower movements of the sarcomere during normal muscle function. In most vertebrate striated muscle types, the comparatively slow release of MgADP (one of the products of MgATP hydrolysis) is thought to be the ratelimiting step (8-13). However, recent studies suggest MgADP release may not be rate limiting for faster muscle types (14-16). If so, we reasoned that a shift in rate-limiting step to another part of the cross-bridge cycle should be most readily apparent in working indirect insect flight muscle, the fastest known muscle type.We had directly shown that myosin isoforms determine Drosophila IFM speed by using genetic engineering methods to substitute a relatively slow embryonic myosin (EMB) for the native fast myosin (IFI) in the IFM (Fig. 1A Inset) (17,18). This substitution transformed the ...

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The myosin motor in muscle generates a smaller and slower working stroke at higher load

Cited by 191 publications

References 27 publications

Is titin a ‘winding filament’? A new twist on muscle contraction

Is titin a ‘winding filament’? A new twist on muscle contraction

Motion of myosin head domains during activation and force development in skeletal muscle

An exceptionally fast actomyosin reaction powers insect flight muscle

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