Direct Modeling of X-Ray Diffraction Pattern from Contracting Skeletal Muscle

Koubassova, Natalia A.; Bershitsky, Sergey Y.; Ferenczi, Michael A.; Tsaturyan, Andrey K.

doi:10.1529/biophysj.107.120832

Cited by 24 publications

(50 citation statements)

References 47 publications

(74 reference statements)

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“…These calculations indicate that the increase in the number of actin-bound heads and the simultaneous decrease in the A1 intensity upon stretch can only be explained if stretch induces an unlocking of stereo-specifically bound heads as was suggested by our ‘roll and lock’ model [12]. The newly formed heads also do not bind actin in a strong, stereo-specific manner, because if they did, the A1 intensity would rise correspondingly.…”

Section: Resultsmentioning

confidence: 60%

Why Muscle is an Efficient Shock Absorber

Ferenczi

Bershitsky

Koubassova³

et al. 2014

PLoS ONE

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Skeletal muscles power body movement by converting free energy of ATP hydrolysis into mechanical work. During the landing phase of running or jumping some activated skeletal muscles are subjected to stretch. Upon stretch they absorb body energy quickly and effectively thus protecting joints and bones from impact damage. This is achieved because during lengthening, skeletal muscle bears higher force and has higher instantaneous stiffness than during isometric contraction, and yet consumes very little ATP. We wish to understand how the actomyosin molecules change their structure and interaction to implement these physiologically useful mechanical and thermodynamical properties. We monitored changes in the low angle x-ray diffraction pattern of rabbit skeletal muscle fibers during ramp stretch compared to those during isometric contraction at physiological temperature using synchrotron radiation. The intensities of the off-meridional layer lines and fine interference structure of the meridional M3 myosin x-ray reflection were resolved. Mechanical and structural data show that upon stretch the fraction of actin-bound myosin heads is higher than during isometric contraction. On the other hand, the intensities of the actin layer lines are lower than during isometric contraction. Taken together, these results suggest that during stretch, a significant fraction of actin-bound heads is bound non-stereo-specifically, i.e. they are disordered azimuthally although stiff axially. As the strong or stereo-specific myosin binding to actin is necessary for actin activation of the myosin ATPase, this finding explains the low metabolic cost of energy absorption by muscle during the landing phase of locomotion.

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Section: Resultsmentioning

confidence: 60%

Why Muscle is an Efficient Shock Absorber

Ferenczi

Bershitsky

Koubassova³

et al. 2014

PLoS ONE

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“…There is some uncertainty about the application of the relationship between f A,PF and I AL1 relative to rigor in the model of Koubassova et al ( figure 6A in ref. 21) because their value of I AL1 in the absence of strongly bound motors is much less than that observed in trabeculae in diastole, and the relationship has a significantly lower slope at the lower extreme of I AL1 . Depending on the interpretation of the diastolic AL1, the resulting estimate of f A at peak force is about 0.10.…”

Section: Methodsmentioning

confidence: 84%

Myosin filament-based regulation of the dynamics of contraction in heart muscle

Brunello

Fusi

Ghisleni

et al. 2020

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

109

150

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Myosin-based mechanisms are increasingly recognized as supplementing their better-known actin-based counterparts to control the strength and time course of contraction in both skeletal and heart muscle. Here we use synchrotron small-angle X-ray diffraction to determine the structural dynamics of local domains of the myosin filament during contraction of heart muscle. We show that, although myosin motors throughout the filament contribute to force development, only about 10% of the motors in each filament bear the peak force, and these are confined to the filament domain containing myosin binding protein-C, the "C-zone." Myosin motors in domains further from the filament midpoint are likely to be activated and inactivated first in each contraction. Inactivated myosin motors are folded against the filament core, and a subset of folded motors lie on the helical tracks described previously. These helically ordered motors are also likely to be confined to the C-zone, and the associated motor conformation reforms only slowly during relaxation. Myosin filament stress-sensing determines the strength and time course of contraction in conjunction with actin-based regulation. These results establish the fundamental roles of myosin filament domains and the associated motor conformations in controlling the strength and dynamics of contraction in heart muscle, enabling those structures to be targeted to develop new therapies for heart disease.heart muscle | myosin motor | muscle regulation | myosin-binding protein C T he pumping action of the heart is driven by rhythmic contractions of its muscular walls. The healthy heart continuously optimizes the strength and time course of contraction by modulating the calcium transient that triggers the heartbeat and the phosphorylation levels of multiple proteins, including components of the myosin and actin filaments that drive contraction, and by direct mechanical feedback (1-4). These signaling pathways alter contractility by changing the structures of the contractile filaments through downstream effector mechanisms that remain poorly understood. For many years attention was focused on actin filament-based regulation and its link to intracellular calcium signaling (1); more recently it became clear, partly by extrapolation from studies on skeletal muscle (5-9), that myosin filamentbased regulation also plays an important role. Moreover, myosinbased regulation is perturbed in heart disease (10, 11), and has been increasingly targeted for the development of novel therapies to treat the failing heart (12). Such efforts have however been impeded by limited knowledge about the action of myosin-based regulation on the timescale of the heartbeat: that is, about mechanisms that operate much faster than kinase signaling (3,4). Two leading candidate mechanisms of this type emerged from studies of skeletal muscle: direct mechanosensing by the myosin filaments (6, 7), and interfilament signaling by myosin binding protein-C (6,13). Although several studies have suggested that these mechanisms are ...

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“…no crossbridge detachment or attachment occurs. Otherwise changes in the number of attached myosin heads or in the dispersion of their positions from the 14.5 nm repeat strongly affect I M3 (63,78). All four factors: the number of myosin heads bound to actin, their shape, the standard deviation of their axial positions from the 14.5 nm repeat, and axial misalignment of the neighboring myosin filaments are important determinants of the intensity of the M3 (and possibly other) myosin meridional reflections.…”

Section: Thick Filament Reflectionsmentioning

confidence: 99%

Insight into the actin-myosin motor from x-ray diffraction on muscle

Bershitsky

Ferenczi²,

Koubassova³

et al. 2009

Front Biosci

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The origin of reflections in the x-ray diffraction pattern from striated muscle and their use for understanding the structural organization of the contractile machinery are presented and discussed. Results of x-ray diffraction experiments obtained by a number of research groups using a variety of protocols revealed structural changes in contracting muscles which are interpreted in terms of molecular movements that underlie force generation. Some of these data are in line with the widely accepted 'lever arm' hypothesis which links force generation to a tilt of the light chain domain of the myosin head with respect to its motor domain. However, changes in the layer line intensities observed in response to various perturbations cannot be explained by tilting of the lever arm. Such changes, first revealed in response to temperature jumps, are interpreted as a transition of non-stereo-specifically attached myosin heads to a stereo-specifically bound state. The new 'roll and lock' model considers force-generation as a two-stage process: initial stereo-specific locking of myosin heads on actin is followed by the lever arm tilt.

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Direct Modeling of X-Ray Diffraction Pattern from Contracting Skeletal Muscle

Cited by 24 publications

References 47 publications

Why Muscle is an Efficient Shock Absorber

Why Muscle is an Efficient Shock Absorber

Myosin filament-based regulation of the dynamics of contraction in heart muscle

Insight into the actin-myosin motor from x-ray diffraction on muscle

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