The proposed mechanisms of skeletal muscle contraction: possible uncertainties in the interpretation of the data

Introduction The works of AV Hill and coworkers, AF Huxley and followers, Eisenberg and coworkers, Lombardi and coworkers are rapidly sketched. This hypothesis discusses the possible uncertainties in the interpretation of data in proposed mechanisms of skeletal muscle contraction. The hypothesis In the Huxley-Simmons model, the elastic element must be stretched by one-dimensional fluctuations (Brownian motions) before any chemical change in state. The transition rates are made realistic by assuming that three or more attached states are necessary. Evaluation of hypothesis Some of the concepts generally accepted in the models of muscle contraction are cast in doubt. They are: the lack of consideration of the water–protein interactions; the belief that viscosity is irrelevant in the economy of muscle contraction; the concept of the drag stroke; the significance of the Huxley-Simmons manoeuvre; the possible interference of the equipment on the measurements; and the lack of consideration of the acceleration of the load. Conclusion The lack of consideration of the above items may compromise the correct building of the model of muscle contraction. Introduction Hill’s work AV Hill and coworkers investigated muscle contraction for more than 40 years. The beauty of their work is that the mechanical measurements were always accompanied by thermodynamic measurements. As a matter of fact, contraction velocity, tension, work produced, energy output and heat released were always concomitantly measured. Two fundamental concepts were established: 1) the relation between the contraction velocity and the tension produced. Hill’s equation1 (Figure 1): (P + a) (v + b) = (P0 + a) b where, a and b are constants and 2) that the extra heat produced in shortening a given distance varies with the load, so that the constant α of the heat of shortening for frog sartorii at 0°C, is given by2 (Figure 2): α = 0.16 (± 0.015) P0 + 0.18 (± 0.027) P The sliding filament model In the initial hypothesis of AF Huxley3, the amplitude of the power stroke was a function of the available thermal energy. It was also assumed that at maximum velocity, where tension equals zero, the net positive force exerted by myosin heads attached in the power stroke equals the net negative force exerted by heads that have been carried into the drag-stroke region. In a second model, AF Huxley and Simmons4 assumed that, after attachment, the cross-bridges rotate from one to the next of a few positions with progressively lower potential energy while stretching a 40 nm long elastic linkage. At the end of the rotation, the detachment of myosin head was caused by the hydrolysis of ATP. The model of Eisenberg et al. In the model of Huxley and Simmons4, the elastic element must be stretched by one-dimensional fluctuations (Brownian motion) before any transition may occur, as a consequence, to make the transition rates realistic, three or more attached states are necessary. Eisenberg et al.5, on the contrary, assume that in the transitions, elasticity and chemical changes of state are linked. The conformational change of the attached cross-bridge therefore affects both the free energy and the force exerted by the crossbridge. Further, the model of Eisenberg et al.5 predicts that the number of the attached cross-bridges (and not their force) decreases with the shortening velocity. The length of the power stroke and the force delivered by the motors The response of the cross-bridge to the same output of mechanical energy may be threefold: (1) weak force and large motion, (2) strong force and short motion and (3) variable force/distance ratio depending on the load. According to AF Huxley, the response of the cross-bridge is of the weak force – large motion3, with a ~10 nm power stroke4. It is, however, most likely that that the force/ distance ratio changes with the load. This possibility was first formulated theoretically by Worthington and Elliott6, then experimentally by Piazzesi et al.7, who proposed the step size to decrease from 7 nm at zero load to 4 nm at 80% of the isometric load. * Corresponding author Email: enrico.grazi@unife.it Dipartimento di Biochimica e Biologia Molecolare, Universita di Ferrara, Via Borsari 46, 44100 Ferrara, Italy