Mechanical control of the rising phase of contraction of frog skeletal and cardiac muscle

The effect of shortening on contractile activity was studied in experiments in which shortening during the rising phase of an isotonic contraction was suddenly stopped. At the same muscle length and the same time after stimulation the rise in tension was much faster, if preceded by shortening, than during an isometric contraction, demonstrating an increase in contractile activity. In this experiment the rate of tension rise determined in various phases of contraction was proportional to the rate of isotonic shortening at the same time after stimulation. Therefore, the time course of the isotonic rising phase could be derived from the tension rise after shortening. The rate of isotonic shortening was found to be unrelated to the tension generated at various lengths and to correspond closely to the activation process induced by shortening. The length response explains differences between isotonic and isometric contractions with regard to energy release (Fenn effect) and time relations. These results extend previous work which showed that shortening during later phases of a twitch prolongs, while lengthening abbreviates contraction. Thus the length responses, which have been called shortening activation and lengthening deactivation, control activity throughout an isotonic twitch.     

Energy Production in Cardiac Isotonic Contractions

The energy output of rabbit papillary muscle is examined and it is shown that there is more energy liberated in an afterloaded isotonic contraction than in an "equivalent" isometric contraction. This statement holds true regardless of whether equivalence is based on the proposition that tension or the time integral of tension is the best index of muscle energy expenditure. Besides the external work performed there is additional heat production in isotonic contractions and this heat increases as the afterload is decreased. The additional heat is more evident when tension rather than the time integral of tension is made the determinant of energy expenditure. It is shown in single contractions that the rate of isotonic heat production, regardless of afterload size, never exceeds the heat rate recorded in an isometric contraction at the same initial length. Experiments reveal no simple linear correlation between isotonic energy output and contractile element work. Problems associated with the compartmentalization of the energy output of a contraction are discussed.     

Myokinase and contractile function of glycerinated muscle fibers

Glycerinated rabbit psoas muscle fibers containing native CPK, ATPase, and myokinase activities were used and isometric contraction and relaxation responses to either ADP or ATP + CP or to ATP alone in the presence and absence of P1, P5-di(adenosine-5'-pentaphosphate), a myokinase inhibitor, were compared. In previous (14) work it was shown that CP generated more efficient and faster contraction and relaxation of glycerinated muscle fibers than ATP. The present work deals with the role of myokinase in the differential response of fibers to CP and ATP. Inhibition of the myokinase activity of these fibers caused slight diminution of the rate of contraction at physiological concentrations of ATP. Uninhibited fibers were not able to reach maximum contraction, because the tension began to drop gradually even in the presence of Ca2+. Addition of Ap5A permitted maximum contraction and the ability to stay at the contracted state. In the case of CP + adenosine nucleotides (ATP or ADP), myokinase activity decreased the rate of tension development which was statistically significant after 5-7 sec of contraction. Thus, a higher tension was obtainable when myokinase was inhibited. At high concentration of adenine nucleotides (greater than 2 mM) and in the absence of Ap5A, not only the maximum tension never was reached, but a spontaneous drop in tension was observed before addition of EGTA, as was seen with ATP alone. Relaxation was faster and more complete in the presence of uninhibited myokinase activity except that the ADP was low (125 mM). These observations provide further evidence for a close functional interaction of these three enzymes in the mechanism of contraction and relaxation, giving further support to the notion of the creatine-phosphocreatine energy shuttle.     

Effects of excitation-contraction uncoupling by stretch and hypertonicity on metabolism and tension in single frog muscle fibers

Metabolism and tension were examined in single fibers of the semitendinosus muscle of Rana pipiens at 15 degree C after excitation- contraction uncoupling by stretch and hypertonicity. Interrupted tetanic stimulation at 20 HZ for 150 s, of control fibers in isotonic Ringer at a rest sarcomere length (SL) of 2.3 micrometers, resulted in a steadily declining tension, stimulated glycolysis, and significantly reduced fiber phosphocreatine (PCr) and ATP concentrations. Stretching resting muscle fibers to an SL of 4.7 micrometers did not alter metabolite concentrations, but glucose-6-phosphate rose and PCr fell markedly when the stretched fibers were stimulated tetanically, although tension was absent. Immersion of untetanized fibers in 2.5 X isotonic Ringer produced a transient rise in resting tension, an increase in glucose-6-phosphate, and a significant reduction in PCr. During the transient rise in resting tension, PCr consumption per unit of tension-time integral was the same as that in fibers stimulated tetanically in isotonic Ringer. Tetanization of fibers in hypertonic solution did not further alter metabolite concentrations or produce tension. The results indicate that exposure to hypertonicity induces an increase in both tension and consumption of high-energy phosphate bonds (approximately P) in resting fibers, but stretch does not. during tetanic stimulation, stretch interferes with contraction but does not prevent activation, whereas hypertonicity inhibits activation as well as contraction.     

ATP consumption and efficiency of human single muscle fibers with different myosin isoform composition

Chemomechanical transduction was studied in single fibers isolated from human skeletal muscle containing different myosin isoforms. Permeabilized fibers were activated by laser-pulse photolytic release of 1.5 mM ATP from p(3)-1-(2-nitrophenyl)ethylester of ATP. The ATP hydrolysis rate in the muscle fibers was determined with a fluorescently labeled phosphate-binding protein. The effects of varying load and shortening velocity during contraction were investigated. The myosin isoform composition was determined in each fiber by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. At 12 degrees C large variations (three- to fourfold) were found between slow and fast (2A and 2A-2B) fibers in their maximum shortening velocity, peak power output, velocity at which peak power is produced, isometric ATPase activity, and tension cost. Isometric tension was similar in all fiber groups. The ATP consumption rate increased during shortening in proportion to shortening velocity. At 12 degrees C the maximum efficiency was similar (0.21-0.27) for all fiber types and was reached at a higher speed of shortening for the faster fibers. In all fibers, peak efficiency increased to approximately 0.4 when the temperature was raised from 12 degrees C to 20 degrees C. The results were simulated with a kinetic scheme describing the ATPase cycle, in which the rate constant controlling ADP release is sensitive to the load on the muscle. The main difference between slow and fast fibers was reproduced by increasing the rate constant for the hydrolysis step, which was rate limiting at low loads. Simulation of the effect of increasing temperature required an increase in the force per cross-bridge and an acceleration of the rate constants in the reaction pathway.     

BDM compared with P(i) and low Ca2+ in the cross-bridge reaction initiated by flash photolysis of caged ATP.

Using flash photolysis of caged ATP in skinned muscle fibers from rat psoas, we examined the inhibitory effects of 2,3-butanedione monoxime (BDM) on the contraction kinetics and the rate of ATP hydrolysis of the cross-bridges at approximately 10 degrees C. The hydrolysis rate was estimated from the stiffness records. The effects of BDM were compared with those of orthophosphate (P(i)) and of reduction in [Ca2+] (low Ca2+), and it was found that i) BDM and low Ca2+ inhibited ATPase activity to the same extent as they inhibited the steady tension, whereas P(i) inhibited ATPase activity much less than tension; ii) BDM and P(i) decreased tension per stiffness during the steady contraction more than did low Ca2+; iii) neither BDM nor low Ca2+ affected the initial relaxation of the fiber on release of ATP, but P(i) slightly slowed it; and iv) BDM hardly influenced the rate of contraction development after relaxation, although P(i) and low Ca2+ accelerated it. We concluded that BDM inhibits the Ca(2+)-regulated attachment of the cross-bridges and force-generation of the attached cross-bridges.     

Caldesmon inhibits skeletal actomyosin subfragment-1 ATPase activity and the binding of myosin subfragment-1 to actin

Smooth muscle contraction is controlled in part by the state of phosphorylation of myosin. A recently discovered actin and calmodulin-binding protein, named caldesmon, may also be involved in regulation of smooth muscle contraction. Caldesmon cross-links actin filaments and also inhibits actin-activated ATP hydrolysis by myosin, particularly in the presence of tropomyosin. We have studied the effect of caldesmon on the rate of hydrolysis of ATP by skeletal muscle myosin subfragment-1, a system in which phosphorylation of the myosin is not important in regulation. Caldesmon is a very effective inhibitor of ATP hydrolysis giving up to 95% inhibition. At low ionic strength (approximately 20 mM) this effect does not require smooth muscle tropomyosin, whereas at high ionic strength (approximately 120 mM) tropomyosin enhances the inhibitory activity of caldesmon at low caldesmon concentrations. Cross-linking of actin is not essential for inhibition of ATP hydrolysis to occur since at high ionic strength there is very little cross-linking as determined by a low speed sedimentation assay. Under all conditions examined, the decrease in the rate of ATP hydrolysis is accompanied by a decrease in the binding of myosin subfragment-1 to actin. Furthermore, caldesmon weakens the equilibrium binding of myosin subfragment-1 to actin in the presence of pyrophosphate. We conclude that caldesmon has a general weakening effect on the binding of skeletal muscle myosin subfragment-1 to actin and that this weakening in binding may be responsible for inhibition of ATP hydrolysis.     

The rate of changes in tension within fused tetani of single motor units in rat medial gastrocnemius muscle.

The time course of fused tetani of three main types of motor units: slow (S), fast resistant (FR) and fast fatigable (FF) was studied in the rat medial gastrocnemius. The rate of tension generation and of the relaxation within a tetanus was measured under isometric conditions. These measurements were performed at three points during both the contraction and relaxation: the beginning, the middle and the end of the phase of changes in tension. Significant differences were found in the rate of tension changes between fast and slow units. Comparison of FF and FR units showed less pronounced differences in their rates of the contraction and the relaxation. Moreover, slow units showed significantly greater slowing of both the contraction and relaxation within a tetanus in relation to the speed of their twitch when compared to fast motor units. The rate of changes in tetanic tension correlated to twitch time parameters and to tension generated during twitch or tetanus. The results point out that the well known difference in the speed of twitch contraction between fast and slow units is also visible in their fused tetani.     

The Contractile and Control Sites of Natural Actomyosin

The various contractile and control sites of natural actomyosin gel were studied by comparing the kinetics of ATP hydrolysis with those of gel contraction, measured as an increase in turbidity. Contraction of actomyosin gel seems to require the cooperative reaction of ATP (with Mg) at two different sites. One of these sites catalyzes the hydrolysis of ATP and most probably contributes the driving force for contraction; the binding of ATP to the other site appears to break certain links that retard movement of the gel components. At limiting concentrations of ATP, the rate of contraction seems to depend on the rate of breaking these links as well as on the rate of ATP hydrolysis. But when both sites are saturated, the rate of contraction appears to be limited only by the rate of ATP hydrolysis. In addition to these two contractile sites, there are also two different control sites. At one, the relaxing site, the binding of ATP with Mg inhibits ATP hydrolysis and gel contraction. At the other, the binding of calcium activates contraction by overcoming the inhibitory action of Mg and ATP at the relaxing site. This control system—inhibition by substrate and disinhibition by calcium—can be selectively inactivated by heat and reactivated by dithiothreitol, a disulfide-reducing agent. These observations on the isolated contractile system are discussed in relation to the contraction and relaxation of muscle.     

Intramolecular strain coordinates kinesin stepping behavior along microtubules

Kinesin advances 8 nm along a microtubule per ATP hydrolyzed, but the mechanism responsible for coordinating the enzymatic cycles of kinesin's two identical motor domains remains unresolved. Here, we have tested whether such coordination is mediated by intramolecular tension generated by the "neck linkers," mechanical elements that span between the motor domains. When tension is reduced by extending the neck linkers with artificial peptides, the coupling between ATP hydrolysis and forward stepping is impaired and motor's velocity decreases as a consequence. However, speed recovers to nearly normal levels when external tension is applied by an optical trap. Remarkably, external load also induces bidirectional stepping of an immotile kinesin that lacks its mechanical element (neck linker) and fuel (ATP). Our results indicate that the kinesin motor domain senses and responds to strain in a manner that facilitates its plus-end-directed stepping and communication between its two motor domains.     

The effects of ADP and phosphate on the contraction of muscle fibers.

The products of MgATP hydrolysis bind to the nucleotide site of myosin and thus may be expected to inhibit the contraction of muscle fibers. We measured the effects of phosphate and MgADP on the isometric tensions and isotonic contraction velocities of glycerinated rabbit psoas muscle at 10 degrees C. Addition of phosphate decreased isometric force but did not affect the maximum velocity of shortening. To characterize the effects of ADP on fiber contractions, force-velocity curves were measured for fibers bathed in media containing various concentrations of MgATP (1.5-4 mM) and various concentrations of MgADP (1-4 mM). As the [MgADP]/[MgATP] ratio in the fiber increases, the maximum velocity achieved by the fiber decreases while the isometric tension increases. The inhibition of fiber velocities and the potentiation of fiber tension by MgADP is not altered by the presence of 12 mM phosphate. The concentration of both MgADP and MgATP within the fiber was calculated from the diffusion coefficient for nucleotides within the fiber, and the rate of MgADP production within the fiber. Using the calculated values for the nucleotide concentration inside the fiber, observed values of the maximum contraction velocity could be described, within experimental accuracy, by a model in which MgADP competed with MgATP and inhibited fiber velocity with an effective Ki of 0.2-0.3 mM. The average MgADP level generated by the fiber ATPase activity within the fiber was approximately 0.9 mM. In fatigued fibers MgADP and phosphate levels are known to be elevated, and tension and the maximum velocity of contraction are depressed. The results obtained here suggest that levels of MgADP in fatigued fibers play no role in these decreases in function, but the elevation of both phosphate and H+ is sufficient to account for much of the decrease in tension.     

Continuum rheology of muscle contraction and its application to cardiac contractility.

A set of constitutive equations is proposed to describe the mechanics of contraction of skeletal and heart muscle. Fiber tension is assumed to depend on the degree of chemical activation, the stretch ratio, and the rate of stretching of the fibers. The time rate of change of activation is governed by a differential equation. The proposed constitutive equations are used to model the time courses of isotonic and isometric twitches during contraction and relaxation phases of the muscle response to stimulation. Various contractility indices of the left ventricle are considered next by using the proposed constitutive equations. The present analysis introduces a new interpretation of the index of contractility (dP/dt)/P used in cardiac literature. It is shown that this index may not be related at all to the maximum speed of shortening and that it may be dependent on both preload and afterload. The development of pressure during isovolumetric contraction of the left ventricle is shown to be governed by a differential equation describing the time rate of change of tension during isometric contraction of myocardium fibers.     

Kinetics of ATP hydrolysis and tension production in skinned cardiac muscle of the guinea pig

The kinetics of ATP hydrolysis and tension responses were studied simultaneously in a permeabilized preparation of cardiac tissue of the guinea pig. This was achieved by combining laserflash photolysis of P3-1-(2-nitrophenyl)ethyladenosine 5'-triphosphate ("caged-ATP") and a rapid freezing technique. In the presence of calcium ions, tension increased following the photolytic production of ATP with a half-time of 0.3 s. The timecourse of ATP hydrolysis consisted of an initial rapid phase followed by a steady-state hydrolysis rate of 0.4 s-1, indicating that the rate-limiting step of the ATPase in isometric fibers is slower and subsequent to the nucleotide hydrolysis step: the isometric steady state intermediate is probably an actomyosin-ADP complex. In the absence of calcium ions, rigor tension decreased upon the photolytic production of ATP with a half-time of 0.45 s. The time course of ATP hydrolysis was biphasic with a rapid initial phase of ATP hydrolysis, followed by a steady-state hydrolysis rate which was too slow to measure over the time scale of these experiments (less than 0.04 s-1). A comparison of the results obtained in this study with those reported for rabbit skeletal muscle reveals qualitative similarities between cardiac and skeletal muscle and also quantitative differences in their physiological and kinetic behavior.     

An "active enzyme" muscle model

A new model of skeletal muscle contraction is presented from a unified view of muscle physiology, chemical energetics and newly obtained experimental data concerning actomyosin ATPase in vitro.In this model an interaction between actin and myosin, involving two distinct active sites, is considered to be the essential elementary mechanism for muscle contractions. These two sites are located on myosin. One site, forming a myosin-ADP-P, complex, has stored energy derived from ATP splitting before the beginning of a contraction. Another site, forming a myosin-ATP complex, upon interacting with actin, catalyzes ATP hydrolysis, using a fraction of the stored energy. The hydrolysis at the latter site is responsible for tension development, while the stored energy is released to drive the contractile reaction between actin and myosin unidirectionally. (Thus, the two sites act co-operatively and they can be viewed as forming an active enzyme.)There has been a difficulty in explaining the shortening heat production with apparent lack of corresponding chemical change at the early stage of contraction. The active enzyme model accounts for the shortening heat as the irreversible release of the stored energy. The heat production appears to precede its corresponding ATP splitting for “refueling” which occurs after complete exhaustion of the stored energy, while the actomyosin ATP hydrolysis takes place proportionally to the work. At the macroscopic level, the model is compatible with Hill's tension-velocity and heat relation.     

The relationship between initial creatine phosphate breakdown and recovery oxygen consumption for a single isometric tetanus of the frog sartorius muscle at 20 degrees C

A previous paper (Mahler, M. 1978 J. Gen. Physiol. 71:559--580) describes the time-course of the suprabasal rate of oxygen consumption (delta QO2) in the sartorius muscle of R. pipiens after isometric tetani of 0.1--1.0 s at 20 degrees C. To test whether these were the responses to impulse changes in the rate of ATP hydrolysis, we compared the total suprabasal oxygen consumption during recovery (delta[O2]) with the amount of ATP hydrolyzed during a contraction, measured indirectly as the decrease in creatine phosphate (delta[CP]O). If suprabasal ATP hydrolysis during recovery is negligible in comparison with that during contraction, delta[CP]0/delta[O2] should approximate the P:O2 ratio for oxidative metabolism, which has an expected value of 6.1--6.5. We found: formula; see text. We conclude that in this muscle at 20 degrees C: (a) after a tetanus of 0.2--1.0 s, delta QO2(t) can be considered the response to an impulse increase in the rate of ATP hydrolysis; (b) the reversal during recovery of unidentified exothermic reactions occurring during the contraction (Woledge, R. C. 1971. Prog. Biophys. Mol. Biol. 22:39--74) can be coupled to an ATP hydrolysis that is at most a small fraction of delta[CP]0; (c) the pooled mean for delta[CP]0/delta[O2], 6.58 +/- 0.55, sets an experimental lower bound for the P:O2 ratio in vivo.     

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.     

Generation of force by single-headed myosin.

Myosin has two heads, each of which can interact with actin and ATP. We have investigated the possibility that co-operative interactions occur between the heads by measuring the force generated by single-headed myosin in reconstituted actomyosin threads. Myofibrils were digested with papain, actomyosin was extracted from the myofibrils, and one-headed myosin was purified by cycles of sedimentation with actin. The one-headed myosin was approximately 90 to 95% pure as determined by densitometer scans of polyacrylamide gels run in 20 mm-PP₁ (impurities consisted of 1 to 5% of myosin and 1 to 5% myosin rod). The ATPase activity per mole of single-headed myosin was one half that of myosin under conditions where the activity was activated by Ca²⁺, K⁺ or actin. One-headed myosin could also participate in superprecipitation, although with a rate that was at least one order of magnitude slower than that for myosin. Myosin or one-headed myosin was mixed with actin, threads were formed via extrusion into low ionic strength, and the isometric forces and isotonic velocities generated by the threads were measured. The ratio of the isometric tension produced per head by the one-headed myosin to the isometric tension produced per head by myosin was 1·0 ± 0·1. The maximum velocity of thread contraction for the one-headed myosin was also not different from the control myosin. Thus, the absence of one head does not appear to impair the generation of force or motion by the remaining head.     

Temperature dependence of mammalian muscle contractions and ATPase activities

Isolated rat and mouse extensor digitorum longus (EDL) and soleus muscles were studied under isometric and isotonic conditions at temperatures from approximately 8 degrees -38 degrees C. The rate constant for the exponential rise of tension during an isometric tetanus had a Q10 of approximately 2.5 for all muscles (corresponding to an enthalpy of activation, delta H = 66 kJ/mol, if the rate was determined by a single chemical reaction). The half-contraction time, contraction time, and maximum rate of rise for tension in an isometric twitch and the maximum shortening velocity in an isotonic contraction all had a similar temperature dependence (i.e., delta H approximately 66 kJ/mol). The Mg++ ATPase rates of myofibrils prepared from rat EDL and soleus muscles had a steeper temperature dependence (delta H = 130 kJ/mol), but absolute rates at 20 degrees C were lower than the rate of rise of tension. This suggests that the Mg++ ATPase cycle rate is not limiting for force generation. A substantial fraction of cross-bridges may exist in a resting state that converts to the force-producing state at a rate faster than required to complete the cycle and repopulate the resting state. The temperature dependence for the rate constant of the exponential decay of tension during an isometric twitch or short tetanus (and the half-fall time of a twitch) had a break point at approximately 20 degrees C, with apparent enthalpy values of delta H = 117 kJ/mol below 20 degrees C and delta H = 70 kJ/mol above 20 degrees C. The break point and the values of delta H at high and low temperatures agree closely with published values for the delta H of the sarcoplasmic reticulum (SR) Ca++ ATPase. Thus, the temperature dependence for the relaxation rate of a twitch or a short tetanus is consistent with that for the reabsorption rate of Ca++ into the SR.     

Sliding distance per ATP molecule hydrolyzed by myosin heads during isotonic shortening of skinned muscle fibers.

We measured isotonic sliding distance of single skinned fibers from rabbit psoas muscle when known and limited amounts of ATP were made available to the contractile apparatus. The fibers were immersed in paraffin oil at 20 degrees C, and laser pulse photolysis of caged ATP within the fiber initiated the contraction. The amount of ATP released was measured by photolyzing 3H-ATP within fibers, separating the reaction products by high-pressure liquid chromatography, and then counting the effluent peaks by liquid scintillation. The fiber stiffness was monitored to estimate the proportion of thick and thin filament sites interacting during filament sliding. The interaction distance, Di, defined as the sliding distance while a myosin head interacts with actin in the thin filament per ATP molecule hydrolyzed, was estimated from the shortening distance, the number of ATP molecules hydrolyzed by the myosin heads, and the stiffness. Di increased from 11 to 60 nm as the isotonic tension was reduced from 80% to 6% of the isometric tension. Velocity and Di increased with the concentration of ATP available. As isotonic load was increased, the interaction distance decreased linearly with decrease of the shortening velocity and extrapolated to 8 nm at zero velocity. Extrapolation of the relationship between Di and velocity to saturating ATP concentration suggests that Di reaches 100-190 nm at high shortening velocity. The interaction distance corresponds to the sliding distance while cross-bridges are producing positive (working) force plus the distance while they are dragging (producing negative forces). The results indicate that the working and drag distances increase as the velocity increases. Because Di is larger than the size of either the myosin head or the actin monomer, the results suggest that for each ATPase cycle, a myosin head interacts mechanically with several actin monomers either while working or while producing drag.     

The sliding filament model of muscle contraction. II. The energetic and dynamical predictions of a quantum mechanical transducer model

A theoretical model of a molecular energy transducing unit designed for the production of mechanical work is constructed and its consequences examined and compared with the experimentally determined myothermal and dynamic properties of vertebrate striated muscle. The model rests on a number of independent assumptions which include: the almost instantaneous generation of mechanical force by the occurrence of a radiationless transition between vibronic states of the transducer (crossbridge) at a point of potential energy surface crossing; transmission of this force to the load via the active sites on the thin filament by means of non-bonding repulsive forces, no energy being required for detachment; “detachment” consists of a second radiationless transition at a lower energy point than the first force generating transition, the energy difference appearing largely as work. The method of force generation completely avoids problems such as the “force-rate dilemma” which occur repeatedly in any discussion where state populations are near-Boltzmann and also leads without further arbitrary assumptions to such concepts as “attached but non force-producing states” and strongly position dependent “attachment” and “detachment” rate constants since these can only be appreciable near potential energy surface crossings. The kinetics and energetics of a transducer of this type operating cyclically and converting ATP → ADP + P_i are considered and shown to lead to length-tension and energetic behaviour very similar to that exhibited by vertebrate striated muscle, both for contraction and stretching. The existence of a limiting tension for stretching is predicted by the model as is the decrease of the rate of enthalpy release rate below the isometric value. At the limiting tension the rate of enthalpy release by the transducers is virtually zero, as observed. However, the stretching only inhibits the ATP hydrolysis, the cyclic synthesis from ADP and work being impossible with this model. The response to rapid length step changes automatically contains the asymmetry observed experimentally (with respect to lengthening and shortening) and arbitrary assumptions over and above those giving adequate explanation of the steady-state properties are not required. The asymmetry arises mainly as a consequence of the non-bonded pushing action of the crossbridges. This same assumption predicts the occurrence of an asymmetric thermoelastic ratio for active muscle with respect to stretching and contraction. The quantitative aspects of the model are satisfactory as it simultaneously reconciles the numerical magnitudes of macroscopic quantities such as isometric tension, maximum contraction velocity, limiting tension sustainable on stretching, isometric heat rate and resting heat rate with molecular parameters such as the filament and crossbridge periodicities, molecular vibrational relaxation rates, recurrence times for the radiationless transitions occurring, etc. This is achieved without any parameter optimization and only a very much smaller number of unknown parameters than the number of observed results accounted for. Many of the entities occurring in the model cycle (vibronic states of crossbridges, ATP, etc.) appear to be in one-to-one correspondence with many of the kinetic entities postulated to account for the biochemical kinetic results obtained for the actomyosin ATPase system in vitro. Finally, the rigor state has to be viewed in a different way from the conventional one; on the basis that the present model states which are part of the contraction cycle but sparsely populated during the latter (and hence are of chemical kinetic but not dynamical importance) are heavily populated during the rigor state. The mechanical properties of the rigor state would then be determined by these molecular states which would be very short-lived during the contraction cycle. If this is correct the rigor state could yield much more information about inaccessible parts of the contraction cycle than is presently supposed. The model leads one to expect a rather different response to quick length step changes in the rigor state from that of the active state, in contrast to current interpretations in terms of a large number of attached crossbridges, unable to detach due to the absence of ATP.