Technology and Health Care, 1 (1993) 133-142 0928-7329/93/$06.00 © 1993 Elsevier Science Publishers B.V. All rights reserved

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Mechanism of muscle contraction L. Skubiszak Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Twarda 55, 00-818 Warsaw, Poland (Received 29 June 1993, Accepted 29 June 1993)

Abstract This work is the first attempt to propose a complex model of muscle contraction in which different aspects of the sarcomere shortening are collected into a logical entity. Proposed are some suggestions to answer some fundamental questions concerning the molecular mechanism of muscle contraction, such as the following: "of which part of the myosin molecule does the crossbridge consist?", "how does the crossbridge act?", "what are two heads of the myosin molecule needed for?", "in what way is the metabolic energy of ATP converted into the mechanical work of muscle contraction?", "does the actin filament influence have a passive or active role in the process of muscle contraction?", "what is the role of the third filament - a connecting one?", "in what way is muscle relaxation generated?". Key words: Muscle contraction; Myosin filament; Actin filament; Connecting filament

1. Introduction

At present much detailed knowledge concerning different aspects of muscle contraction has been accumulated. However, the molecular mechanism by which force and motion are generated, i.e. how metabolic energy is converted into mechanical work, still remains one of the major unsolved problem in biology. There are a great number of conceptions about the mechanism of muscle contraction. It seems reasonable to divide all existing models into two groups: so-called crossbridge models and all others. Over the past four decades muscle science has been dominated by the sliding-filament model originally proposed in 1953 by two groups of workers: Huxley and Niedergerke [1], and Huxley

and Hanson [2]. According to this model, muscle changes its overall length by the movement past each other of the two kinds of filaments, the thick one, consisting mainly by the protein myosin, and the thin filament, containing the protein actin. The great majority of present-day workers on muscle accept the hypothesis of Huxley [3] and Huxley and Simmons [4] that movement is generated by crossbridges which result from the attachment of myosin heads with actin monomers. In the course of the last decade it was proven that in relaxed muscle (i.e. ATP excess and Ca 2 + deficit) most of the heads lie along helical paths around the thick filament (one head points up to the myosin filament and the other one, belonging to the same myosin molecule, points down) [5-7]. In transition to the rigor state (Ca 2 +, no ATP), from the relaxed state, on the one hand, the

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cross-links between the thick and thin filaments occur [8,9], and, on the other hand, a clear redistribution of mass can be observed [10-12]: a loss of mass around the thick filament and a gain of mass around the thin one. Upon activation about 30% of the mass of myosin moves away from the vicinity of the thick filament to the vicinity of the thin filament [10,13,14]. In the light of these experimental data, the movement of crossbridges in the space between the two kinds of filaments during muscle contraction and their active role in this process seems to be unquestionable. Simultaneously, it is known that the myosin and actin filaments in vertebrate striat"ed muscle are packed into hexagonal bundles [2,15]. The distance between the adjacent thick and thin filaments is about 13 nm [11,12] and the lengths of the two fragments of myosin molecule from which the crossbridge forms are about 43 nm (so-called subfragment 2, S2) and 16-19 nm (so-called subfragment 1, SI or myosin head), respectively [16,17]. From these facts the question arises: "how do the crossbridges act?". The next problematical question of muscle contraction concerns the role in this process of the two remaining filaments: actin and connecting ones. Recently, more and more experimental works have proved that the force and motion can be produced in the system containing only one immobilized head and actin filament [18-21]. This suggests that the actin filament affects contraction as actively as the myosin one. In the current models, the actin filament has a passive role in force generation. There is evidence accumulated from several laboratories [22-26] that thick filaments are linked to Z-discs by connecting filaments. A major component of the system is the protein titin. Titin had been localized in both the I and A-bands. It is widely accepted that the I-band region of connecting filament is elastic and the A-band region is non-extensible. This fact has not been taken into consideration in any model. The next essential experimental fact concerns conformational changes. Recently, conformational transformations occuring in head and actin globules as well as in the whole thin filament in

different circumstances are being studied by various laboratories [27-29]. The conformational state is coupled with the biochemical properties. For instance, the association of myosin with ADP (MADP) induces strong binding with actin and the complex M-ATP.Pj - weak binding. ATP molecules affect detachment between the myosin and actin. This fact has been taken into acount in some models, e.g. [30,31]. In this work it is attempted for the first time to propose, in as much as possible, a complete model of muscle contraction. In contradiction to the models existing so far, in which a probable mechanism of interaction only between some pair of actin and myosin molecules had been paid serious consideration, the proposed model takes into account a three-dimensional structure of the whole sarcomere and a time-space coupling between structural, biochemical, biophysical and physiological events occuring during muscle contraction in three kinds of myofilaments: the thick, thin and connecting ones. 2. Structure of the thick filament An understanding of the detailed molecular structure of the thick filament and the changes that take place in its structure during muscle contraction is of great importance in comprehending how tension and movement are generated at the molecular level. Unfortunately, while both the structure of myosin and its aggregation properties have been studied in detail [32-36], the existing models of the vertebrate thick filament are not consistent with recently available experimental data. Myosin, of which the thick filament consists, can be proteolitically divided into five characteristic fragments, in succession: light meromyosin (LMM), tail-hinge domain, subfragment 2 (S2), head-hinge domain and two heads (or subfragments 1, S1). In the existing models of how the myosin molecule packs into thick filaments [for review 8,37] the LMM and S2 fragments of myosin molecule lie parallel or near to the filament axis. Because of that, the movement of crossbridges

L. Skubiszak / Technology and Health Care 1 (1993) 133 -142

from the vicinity of the thick filament to the vicinity of the thin filament can be realized only by the rotation of SI with or without S2, i.e. as was proposed by Huxley [4], Huxley [3] or Haselgrove [5]. However, such an idea is, first, in conflict with the real dimensions (mentioned in introduction), secondly, as discussed by Cooke [7], no large rotation in the head-hinge domain takes place with the power stroke, and, finally, in the light of the available experimental data it is difficult to propose any specific phenomena which can coordinate displacement of the SI and S2 fragments past each other. The next problematical question concerns the widely accepted opinion that the thick filament has 3-fold rotational symmetry. Electron micrographs of isolated myosin filaments from various muscles have shown that the crossbridges emerge from the filament shaft in an approximately helical array, with an axial translation of 14.3 nm and axial repeat of 43 nm [for review 8,9,37]. Quantitative mass measurements by electron microscopy [38,39] have strongly supported the occurrence of three pairs of heads at every 14.3 nm axial interval. According to the largely accepted Squire's model of the thick filament [8], three crossbridges belonging to the same "crown" are oriented at 120°. Each successive "crown" is rotated at 40° in relation to the previous one. In fact, two paradoxes arise. First, a series of three successive "crowns" gives a 9-fold distribution of crossbridges around the thick filament. But, according to the Yu experiments [11,12] there is clear 6-fold symmetry around the thick filament. Second, it is not clear what the nine crossbridges are needed for, if only six thin filaments are around the thick filament. Recently, Harford and Squire [40] have proposed that if the crossbridges belonging to some "crown" act singly then the crossbridges belonging to the next two successive "crowns" attach to the thin filament together. But in this instance, new questions arise: "what is the mechanism responsible for coordination of such action?", "how does the structural matching between the thick and thin filaments arise?". As a strong argument for 3-fold symmetry, Squire refers to triangular filament profiles in the so-called H-zone, the bare regions at each side of the M-band [8,41].

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Mechanism of muscle contraction.

This work is the first attempt to propose a complex model of muscle contraction in which different aspects of the sarcomere shortening are collected i...
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