The mechanism of muscle contraction

Knowledge of the mechanism of contraction has been obtained from studies of the interaction of actin and myosin in solution, from an elucidation of the structure of muscle fibers, and from measurements of the mechanics and energetics of fiber contraction. Many of the states and the transition rates between them have been established for the hydrolysis of ATP by actin and myosin subfragments in solution. A major goal is to now understand how the kinetics of this interaction are altered when it occurs in the organized array of the myofibril. Early work on the structure of muscle suggested that changes in the orientation of myosin cross-bridges were responsible for the generation of force. More recently, fluorescent and paramagnetic probes attached to the cross-bridges have suggested that at least some domains of the cross-bridges do not change orientation during force generation. A number of properties of active cross-bridges have been defined by measurements of steady state contractions of fibers and by the transients which follow step changes in fiber length or tension. Taken together these studies have provided firm evidence that force is generated by a cyclic interaction in which a myosin cross-bridge attaches to actin, exerts force through a "powerstroke" of 12 nm, and is then released by the binding of ATP. The mechanism of this interaction at the molecular level remains unknown.     

The mechanism of calcium control of smooth muscle tonic contraction

It has been shown in the experiments carried out on a fraction of inverted vesicles of myometrium sarcolemma that ATP-dependent Ca2+ transport system prevents dissipation of the calcium gradient directed from the intervesicular space outward with subsequent establishment of the stationary level of cation content inside the membrane vesicles (a blocker of electro-controlled calcium channels diltiasems was present in the incubation medium). Ortovanadatean inhibitor of the sarcolemma calcium pump suppressed Ca2+ stationary exchange in the vesicles fraction. The value of calcium stationary content in the vesicle membrane was regulated both by a change of the calcium pump activity (by varying Mg2+ concentration in the ATP-containing incubation medium), and by modification of calcium permeability of the vesicles (by varying concentration of ionophore A-23187 in this medium). In the presence of diltiasem and ortovanadate the Ca2+ basal current entering the myocytes from hyperpotassium washing solution activated the smooth muscle tonic contraction. In the absence of ortovanadate no contractile response was observed. On the basis of the evidence obtained a mechanism of calcium control of myometrium tonic contraction is proposed. According to this mechanism the Ca2+ current entering the unexcited myocytes under physiological conditions is efficiently compensated by the calcium pump of the sarcolemma. The inhibition of the latter (or an increase of the sarcolemma basal calcium permeability) provides further slow transition of the stationary value of Ca2+ concentration in the myoplasm to a new higher level and activation of the smooth muscle contraction accordingly.     

The motor mechanism of myosin V: insights for muscle contraction

It is 50 years since the sliding of actin and myosin filaments was proposed as the basis of force generation and shortening in striated muscle. Although this is now generally accepted, the detailed molecular mechanism of how myosin uses adenosine triphosphate to generate force during its cyclic interaction with actin is only now being unravelled. New insights have come from the unconventional myosins, especially myosin V. Myosin V is kinetically tuned to allow movement on actin filaments as a single molecule, which has led to new kinetic, mechanical and structural data that have filled in missing pieces of the actomyosin-chemo-mechanical transduction puzzle.     

滑行学说解释肌肉收缩机制一疑

阐述了滑行学说解释肌肉收缩过程的基本要点,并就一块肌肉中许多肌小节如何实现同时收缩的问题,进行了初步探讨。     

A new hybrid theory of muscle contraction

This work represents an attempt to find a more complete and adequate interpretation of the phenomenon of muscle contraction than is presently available. Arguments are presented in favour of the idea that the principal groups of existing theories on contraction contain both elements that should be excluded from consideration and elements that are of particular interest to retain. In the present theory, it is accepted that the essential process in muscle contraction is a relative increase in long-range repulsive forces, exerted directly perpendicular to the myofilaments. It is then assumed that these forces of repulsion are converted into forces which shorten the fibre, by way of a passive mechanical action of obliquely arranged cross bridges between the thick and thin filaments. Analysis of important experimental data serves to emphasize the explicative potential of the new theory.     

The theory of sliding filament models for muscle contraction. II. Biochemically-based models of the contraction cycle

A seven-state sliding filament model is proposed which differs from the model of Eisenberg & Greene. It is based on a simplified version of the in-vitro contraction cycle of Stein et al., and also has some desirable dynamical features of the empirical three-state model of Nishiyama & Murase. Appropriate x-dependences for all reaction rates are derived from the transition-state theory. The seventh-state is assumed to be a high-tension intermediate of A.M.ATP, from which direct but x-dependent dissociation can occur. If the final A.M.ATP state has a sufficiently lower tension than that of A.M.ADP.Pi, then the dominant escape path from the intermediate state is shown to be direct dissociation of the actin-myosin bond. This leads to an approximate five-state model for active and relaxed muscle in which A.M and the final A.M.ATP state are omitted.     

An intrinsic mechanism for the oscillatory contraction of muscle

A new model based on the theory of dynamical systems is proposed for the intrinsic random or pscudo-random mechanism underlying certain types of muscular tremor. The active length-tension curve of the individual sarcomere, in conjunction with the passive length-tension relation is a map from length to tension with an observed time delay between length change and resulting tension change. The passive length tension relation is assumed to instantaneously relate this tension change back to a change in length. The stability properties of this iterated interval map are investigated by means of computer simulation and computation of the Lyapunov exponent and the bifurcation tree. The resulting analysis is related to experimental tremor data in the literature in terms of period doubling, bifurcation points, and chaotic behavior. The model appears to have its most fruitful application in understanding the insect type and isometric mammalian types of tremor.     

The efficiency of muscle contraction

When a muscle contracts and shortens against a load, it performs work. The performance of work is fuelled by the expenditure of metabolic energy, more properly quantified as enthalpy (i.e., heat plus work). The ratio of work performed to enthalpy produced provides one measure of efficiency. However, if the primary interest is in the efficiency of the actomyosin cross-bridges, then the metabolic overheads associated with basal metabolism and excitation-contraction coupling, together with those of subsequent metabolic recovery process, must be subtracted from the total heat and work observed. By comparing the cross-bridge work component of the remainder to the Gibbs free energy of hydrolysis of ATP, a measure of thermodynamic efficiency is achieved. We describe and quantify this partitioning process, providing estimates of the efficiencies of selected steps, while discussing the errors that can arise in the process of quantification. The dependence of efficiency on animal species, fibre-type, temperature, and contractile velocity is considered. The effect of contractile velocity on energetics is further examined using a two-state, Huxley-style, mathematical model of cross-bridge cycling that incorporates filament compliance. Simulations suggest only a modest effect of filament compliance on peak efficiency, but progressively larger gains (vis-à-vis the rigid filament case) as contractile velocity approaches Vmax. This effect is attributed primarily to a reduction in the component of energy loss arising from detachment of cross-bridge heads at non-zero strain.     

Muscle contraction: a new interpretation of the transient behaviour of muscle

Piazzesi et al. [G. Piazzesi, L. Lucii, V. Lombardi, J. Physiol. 545 (2002) 145–151] made a study on the muscle transients due to step changes in force using improved time resolution and recorded filament movement and shortening velocities in the four phases. They point to Phase 2 and to Phase 4 (working muscle) and claim that their results do not contradict the swinging-cross-bridge (SCB) model which has a much-quoted constant power stroke of about 150 Å (their value of 70 Å was smaller). Siding with the SCB model, they nevertheless record that the power stroke decreases with load. We are pleased with this experimental result as it conforms to our theory, published in 1996, of an impulsive model with a much smaller step-size distance z (≈20 Å). Using their data we obtain precise interval times and estimates of filament movement in Phase 2 and in working muscle. Our first result is that the time frames (interval times) for Phase 2 are the same as in working muscle. Moreover, we demonstrate that the authors’ data verify the correctness of our calculated z values. There are eight active ATP events in Phase 2 in time frame t compared to one in working muscle in the same time frame t. This gives, for the first time, precise numbers for contractile events. We show that the SCB model is incorrect and our analysis supports the impulsive model with a much smaller filament (zero-load) motion, ≈20 Å per ATP split.     

Co-operative regulation mechanism of muscle contraction: Inter-tropomyosin co-operation model

A new model is presented on the basis of our experimental data and the “tropomyosin-blocking theory” of muscle relaxation to explain the regulation of certain characteristics of muscle contraction, namely that the relation of contraction to pCa is co-operative while calcium-binding is essentially non-cooperative. Our experiments show that end-to-end interactions between adjacent tropomyosin molecules in the groove of the actin helix are essential for the co-operative regulation. The blocking theory says that the tropomyosin molecule in relaxed muscle sterically blocks the myosin attachment site on actin, whereas in contracting muscle it moves to a position away from the attachment site. In this model a concerted movement of tropomyosin molecules, brought about by their end-to-end interactions, is considered to be the essential mechanism of co-operative regulation, and it is assumed that the positional changes of tropomyosin occur primarily when the four calcium binding sites of troponin on the tropomyosin are saturated with calcium. Theoretical analysis of the model, based upon the two-state allosteric model, leads to a Michaelis-Menten equation for the Ca-binding function together with a co-operative equation for the state function, proportional to the contraction or ATPase activity. These two functions fit well the experimental data. With cardiac muscle the slope of the contraction versus pCa curve is slightly less steep than that obtained with skeletal muscle. This difference can be explained by the difference in the number of Ca-binding sites of troponins.