Theory of muscle contraction II. Isotonic contraction

The theory of muscle contraction developed in Part I is extended to non-isometric cases. The basic feature of the approach is the strong viscous coupling of the movement of the counterionic (K⁺) layer with the movement of I-filaments. The surface conductance of the K⁺ layer governs the flux of H⁺ along the I-filaments which in turns regulates the rate of ATP hydrolysis. The energy output of the muscle becomes the function of its mechanical activity. By assuming linear dependence of the K⁺ layer's surface conductance on the velocity of shortening Hill's equation has been derived. With a set of reasonably chosen values of the basic parameters of the theory the values of Hill's constants have been computed. The theory has been also shown to provide the observed dependence of the isometric tension on the degree of the myofilamental overlap.     

Theory of muscle contraction: I. Isometric contraction

For each molecule of ATP hydrolyzed by the ATPase at the subfragment 1 of the heavy meromyosin, one H⁺ is produced and remains associated with the myosin heads until a contact with the G-actins of the I-filaments is established. This contact is brought about by the calcium ions released in the sarcomeres by the sarcoplasmic reticulum at the arrival of nerve impulses. A rapid flux of protons along the I-filaments towards the Z-membrane down the concentration gradient leads to the buildup of a diffusion potential which in turn causes a charge-compensating movement of the diffused cationic layer around the I-filaments in the opposite direction. The latter movement exerts a viscous drag on the actins and tends to move the I-filaments deeper into the inter-A-filament spaces towards the M-line. A consistent and straightforward theory of muscular contraction is developed on these lines. The value of the isometric tension in striated muscle fiber of frog at slack length calculated on the basis of this theory agrees well with the measured value.     

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.     

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.     

Smooth muscle contraction and relaxation

This brief review serves as a refresher on smooth muscle physiology for those educators who teach in medical and graduate courses of physiology. Additionally, those professionals who are in need of an update on smooth muscle physiology may find this review to be useful. Smooth muscle lacks the striations characteristic of cardiac and skeletal muscle. Layers of smooth muscle cells line the walls of various organs and tubes in the body, and the contractile function of smooth muscle is not under voluntary control. Contractile activity in smooth muscle is initiated by a Ca(2+)-calmodulin interaction to stimulate phosphorylation of the light chain of myosin. Ca(2+) sensitization of the contractile proteins is signaled by the RhoA/Rho kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase, thereby maintaining force generation. Removal of Ca(2+) from the cytosol and stimulation of myosin phosphatase initiate the process of smooth muscle relaxation.     

An energetic model of muscle contraction

Initial energy utilization in the twitch is visualized as the result of the activity of two distinct processes. The first is the calcium-pumping activity of the sarcoplasmic reticulum, which has a constant energy requirement under normal conditions. The second is the chemomechanical transduction process consisting of a variable number of quantal contractile events, each with a fixed enthalpy equal to the molecular enthalpy of adenosine triphosphate (ATP) hydrolysis in vivo. This enthalpy appears either as heat or as contractile element work. Total enthalpy varies according to the number of quantal contractile events that occur in the twitch cycle. The basis of the variation is suggested to be velocity-dependent activity of the actomyosin ATPase, allowing more quantal events to occur in a contraction cycle when shortening occurs. The classical designation “activation heat” is held to be appropriate for the first process. The partition of the enthalpy of the second process that is currently in vogue is held to be misleading and a new formulation is suggested in which the properties of the quantal contractile event are reflected in general terms. The formulation of the proposed transduction model represents a conceptual return to the viscoelastic theory, but at a quantal level. The model can explain the results of the preceding paper and is adaptable to different muscles without having to postulate fundamental differences in energy utilization.     

Nox regulation of smooth muscle contraction

The catalytic subunit gp91phox (Nox2) of the NADPH oxidase of mammalian phagocytes is activated by microbes and immune mediators to produce large amounts of reactive oxygen species (ROS) which participate in microbial killing. Homologs of gp91phox, the Nox and Duox enzymes, were recently described in a range of organisms, including plants, vertebrates, and invertebrates such as Drosophila melanogaster. While their enzymology and cell biology are being extensively studied in many laboratories, little is known about in vivo functions of Noxes. Here, we establish and use an inducible system for RNAi to discover functions of dNox, an ortholog of human Nox5 in Drosophila. We report here that depletion of dNox in musculature causes retention of mature eggs within ovaries, leading to female sterility. In dNox-depleted ovaries and ovaries treated with a Nox inhibitor, muscular contractions induced by the neuropeptide proctolin are markedly inhibited. This functional defect results from a requirement for dNox-for the proctolin-induced calcium flux in Drosophila ovaries. Thus, these studies demonstrate a novel biological role for Nox-generated ROS in mediating agonist-induced calcium flux and smooth muscle contraction.