Holmes, Kenneth C.
Kenneth C. Holmes
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Introduction to Muscle Contraction

Introduction to Muscle Contraction, Part 1

A primary aim of the Department of Biophysics since its foundation in 1968 has been to understand in physiochemical terms the molecular mechanism by which muscles produce force. Muscle contraction involves the cyclic interaction of the proteins myosin and actin, often pictured as the rowing of the myosin and actin filaments past each other, using the hydrolysis of ATP as a source of energy. We study the structures of actin and myosin at atomic and near-atomic resolution by protein crystallography, electron microscopy and X-ray fibre diffraction.

As a supplementary technique for studying mobility we also use NMR. We study myosins from various sources and with a varity of bound nucleotide analogues, also in combination with site-directed mutagenesis. A biochemistry group which specializes in the expression of proteins in the cellular slime mould dictyostelium uses enzyme kinetics and in vitro motility assays to guage the effects of mutagenesis. The most interesting cases are then analysed by x-ray crystallography. This project is part of an international collaboration.

The last two years have seen dramatic progress in our understanding of the molecular basis of muscle contraction and indeed we now have considerable understanding of the processes involved in myosin-based motility. The crystallography goup studies other proteins as well, in particular on those which, like myosin, involve the processing of nucleotides.

Research on muscle contraction goes back to the Greeks

Understanding muscle contraction answers one of the fundamental questions posed in classical times, namely the nature of the spiritus animalis. The spiritus animalis was an intrinsic property of living things. Erasistratus (3rd century B.C.) of the Alexandrian school associated the spiritus animalis with the muscles. The pneuma was thought to course along the nerves and make the muscles swell and shorten. In the beginning of the 2nd. century A.D. Galen, the last classical physiologist took over and expanded these ideas introducing a primitive metabolism involving the four humours. Furthermore, Galen made a detailed anatomical examination of muscles and understood that they worked in antagonistic pairs, and that the heart was a muscle for pushing blood into the arteries. In the ensuing millenium nothing much happened and even Galen's insight that muscles pull rather than push seems to have been forgotten, since at the beginning of the ¢16, on the basis of his own anatomical examinations Leonardo da Vinci wrote:

Perchè l'ufizio del musculo è di tirare e non di spingere.

A few years later Vesalius used the phrase Machina Carnis to underline the fact that the production of force resided in the flesh (muscle) itself, and in the early ¢16 Descartes proposed a neuromuscular machine not unlike that of Erasistratus: the nerves carry a fluid from the pineal gland (the seat of the soul) to the muscles which makes them swell and shorten. A little later, Swammerdam was to show that muscles contract at constant volume which invalidated this whole class of pneumatic theories. However, other mechanical models were soon proposed. Alongside such mechanical thinking, however, vitalism survived into the ¢19th., and one needed the whole fabric of metabolic biochemistry and thermodynamics to support the concept that muscle is a chemical machine driven by isothermal combustion which was first articulated by von Helmholtz.

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