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We have measured the force-velocity curves of glycerinated rabbit psoas fibers over a range of ATP concentration from 2.5 microM to 5 mM. As the ATP concentration is increased, the isometric tension increases to a maximum around 50 microM, then decreases to a plateau at 70% of the maximum by 1 mM ATP. At low ATP concentrations the maximum velocity of contraction is low and increases with increasing ATP, reaching a plateau at approximately 2 lengths per second by 1 mM ATP. Our studies suggest that the binding of ATP dissociates the myosin head from actin in the contracting muscle, a reaction similar to that seen in solution. We have constructed models of the actin-myosin-nucleotide interactions based on a kinetic scheme derived from solution studies. The fit of these models to the data shows that the rates of some reactions in the fiber must be considerably different from the rates of the analogous reactions in solution. The data is best fit by models in which head attachment occurs rapidly at the beginning of a power stroke, head detachment occurs rapidly at the end of the power stroke, and the force produced by a myosin head in a power stroke is independent of velocity.
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PMID:Contraction of glycerinated muscle fibers as a function of the ATP concentration. 26 49

1. The effects of single and double cycles of stretch and release on the tension response and relative sliding movement of the actin and myosin filaments in active frog's muscle were investigated. 2. The cross-bridges linking the filaments together are able to accommodate a greater range of filament displacement before becoming detached during a second cycle stretch, providing it commences without delay following the preceding release: sarcomere 'give' then occurs for displacements of around 18 nm, as compared with 12 nm for a first cycle stretch. It is postulated that the difference arises because the myosin heads adopt different 'preferred' positions in the isometric steady-state and at the end of a previous release. 3. Muscle length-tension loops were recorded and used to measure the energy absorbed when a muscle is subjected to cycles of stretch and release. The work absorbed per unit length change increases with increasing displacement of the cross-bridges from their initial (isometric) steady-state position, up to the point at which sarcomere 'give' occurs (S2); thereafter it remains constant. 4. More work is absorbed during the first cycle of a double stretch-release combination than during the second. The greater amount absorbed during the first cycle is associated with a correspondingly greater amount of filament sliding in the period following sarcomere 'give'. Sarcomere length-tension loops were constructed and these showed that not less than 80-85% of the work done on a muscle is absorbed by the sarcomeres themselves. 5. A greater amount of work is done on stretching up to (but not beyond) S2 during second cycle stretch as compared to a first. The difference amounts about 1 mJ.m-2 per half-sarcomere. 6. The results are compatible with the mechanism for force production proposed by Huxley & Simmons (1973), in which each myosin head generates force in a number of stepping movements, from one attached state to another. It is concluded that (a) during an unloaded isotonic contraction the working 'stroke' of the head would result in a 10-13 nm relative sliding movement of the filaments, and (b) the potential energy difference separating the two 'preferred' states is 6-9.6 kT per cross-bridge, or 3-4.8 kT per S-1 sub-units, assuming that each one interacts simultaneously with the actin filament.
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PMID:Filament sliding and energy absorbed by the cross-bridge in active muscle subjected to cycical length changes. 30 34

It is assumed that the back stroke of myosin bridges in a contracting fibre is determined by nucleotide binding. Then an inhibition of actomyosin dissociation can lead to the shortening of the thick filaments. Possible existence of a protein control system, suppressing this dissociation is discussed.
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PMID:[Are the reciprocal sliding of protofibrils and the shortening of thick filaments during muscle contraction based on a common molecular mechanism?]. 96 1

Since the proposal and rapid acceptance of the sliding-filament theory in 1953-1954, numerous suggestions have been made for the cause of the sliding movement. When the amount of overlap is varied by altering the initial length, the maximum tension is directly proportional to, but the speed of shortening under zero load is independent of, the amount of overlap. This suggests strongly that a relative force between thick and thin filaments is produced by independent force-generators distributed within each overlap zone. These force-generators are identified with projections (cross-bridges) on the thick filament, each consisting of part of a myosin molecule. Measurements of the 'tension transients' when the length of a stimulated muscle fibre is suddenly altered show that the range of action of each cross-bridge is 10-15 nm. The travel within a single contraction may be many times greater, so each cross-bridge must act cyclically by attaching, exerting a force and detaching. Details of the tension transients suggest that each cross-bridge makes its movement in two or three steps, each with a potential energy change a few times kT. Each cross-bridge contains also an elastic element in series. It is sufficient, on present evidence, to postulate that the only action of ATP is to dissociate the cross-bridge from the thin filament after it has completed its stroke.
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PMID:The origin of force in skeletal muscle. 109 17

In muscle fibres labelled with iodoacetamidotetramethylrhodamine at Cys707 of the myosin heavy chain, the probes have been reported to change orientation when the fibre is activated, relaxed or put into rigor. In order to test whether these motions are indications of the cross-bridge power stroke, we monitored tension and linear dichroism of the probes in single glycerol-extracted fibres of rabbit psoas muscle during mechanical transients initiated by laser pulse photolysis of caged ATP and caged ADP. In rigor dichroism is negative, indicating average probe absorption dipole moments oriented more than 54.7 degrees away from the fibre axis. During activation from rigor induced by photoliberation of ATP from caged ATP in the presence of calcium, the dichroism reversed sign promptly (half-time 12.5 ms for 500 microM-ATP) upon release of ATP, but then changed only slightly during tension development 20 to 100 milliseconds later. During the onset of rigor following transfer of the fibre from an ATP-containing relaxing solution to a rigor medium lacking ATP, force generation preceded the change in dichroism. The dichroism change occurred slowly (half-time 47 s), because binding of ADP to sites within the muscle fibre limited its rate of diffusion out of the fibre. When ADP was introduced or removed, the dichroism transient was similar in time course and magnitude to that obtained after the introduction or removal of ATP. Neither adding nor removing ADP produced substantial changes in force. These results demonstrate that orientation of the rhodamine probes on the myosin head reflects mainly structural changes linked to nucleotide binding and release, rather than rotation of the cross-bridge during force generation.
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PMID:Transients in orientation of a fluorescent cross-bridge probe following photolysis of caged nucleotides in skeletal muscle fibres. 153 Sep 78

Maximum heart rates (HR) of three soricine shrews and six other small mammals were measured in response to a single supramaximal dose of isoproterenol (Iso) under urethan anesthesia. The highest HR, 1,043 +/- 66 (SD) beats/min (n = 3), was in least shrew (Sorex minutus, mean body mass 3.02 +/- 0.81 g). Maximum HRs of common shrew (Sorex araneus, 7.16 +/- 1.54 g) and water shrew (Neomys fodiens, 12.80 +/- 1.54 g) were 938 +/- 29 (n = 7) and 887 +/- 21 (n = 6), respectively. In general, maximum HRs of soricine shrews and other small wild mammals followed the common mammalian pattern, fHmax/Iso = 443 x Mb-0.14, determined by body size. The exponent for this equation is smaller than that of resting HR (-0.25) (Stahl, J. Appl. Physiol. 22: 453-460, 1967), predicting crossover at approximately 3 g body mass. However, resting HRs of small mammals were clearly lower than expected on the basis of body mass. Lowering resting HR below the common mammalian level, with concomitant increase in stroke volume, seems to be a prerequisite for small mammals to regulate cardiac output against the ceiling of maximum HR. Electrophoretic analysis showed that the myosin of shrew ventricles is different from those of rodent species. In native conditions, shrew myosin, designated V1', migrated faster than the V3 and V1 forms of rat heart. On SDS gradient gel the single heavy chain of shrew myosin migrated slower than the alpha- or beta-chains of rat ventricle. Differences in the molecular weight of light chains were also noted between small mammals. Despite the notable differences in myosin composition, myosin-ATPase activity of the shrew hearts was similar to that of mouse and rat heart. Because duration of isometric contraction was inversely related to resting and maximum HRs, it was concluded that in the small mammals rate and duration of contraction are determined mainly by the release and uptake rate of myoplasmic Ca2+ and less by myosin-ATPase activity.
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PMID:Maximum heart rate of soricine shrews: correlation with contractile properties and myosin composition. 153 6

At the molecular level, muscle contraction is the result of cyclic interaction between myosin crossbridges, which extend from the thick filament, and the thin filament, which consists mainly of actin. The energy for work done by a single crossbridge during a cycle of attachment, generation of force, shortening and detachment is believed to be coupled to the hydrolysis of one molecule of ATP. The distance the actin filament slides relative to the myosin filament in one crossbridge cycle has been estimated as 12 nm by step-length perturbation studies on single fibres from frog muscle. The 'mechanical' power stroke of the attached crossbridge can therefore be defined as 12-nm shortening with a force profile like that shown by the quick recovery of force following a length perturbation. According to this definition, power strokes cannot be repeated faster than the overall ATPase rate. Here, however, we show that the power stroke can be regenerated much faster than expected from the ATPase rate. This contradiction can be resolved if, in the shortening muscle, the free energy of ATP hydrolysis is used in several actin-myosin interactions consisting of elementary power strokes each of 5-10 nm.
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PMID:Rapid regeneration of the actin-myosin power stroke in contracting muscle. 153 50

Motor proteins such as myosin, dynein and kinesin use the free energy of ATP hydrolysis to produce force or motion, but despite recent progress their molecular mechanism is unknown. The best characterized system is the myosin motor which moves actin filaments in muscle. When an active muscle fibre is rapidly shortened the force first decreases, then partially recovers over the next few milliseconds. This elementary force-generating process is thought to be due to a structural 'working stroke' in the myosin head domain, although structural studies have not provided definitive support for this. X-ray diffraction has shown that shortening steps produce a large decrease in the intensity of the 14.5 nm reflection arising from the axial repeat of the myosin heads along the filaments. This was interpreted as a structural change at the end of the working stroke, but the techniques then available did not allow temporal resolution of the elementary force-generating process itself. Using improved measurement techniques, we show here that myosin heads move by about 10 nm with the same time course as the elementary force-generating process.
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PMID:Myosin head movements are synchronous with the elementary force-generating process in muscle. 157 64

The possibility of a super-coiling of the thin filament is studied. The bimetallic super-coiling might contribute to the power-stroke. The calculation of the axial shortening of the proposed super-coiling leads to a very surprising geometric fitting: the maximal axial shortening of the super-coiling, without any loop, of the thin filament segment (38.5 nm) is equal to the axial repeat of cross-bridges (14 nm). According to the present model, the sarcomere shortening is caused by the axial shortening of the super-coiled actin filament. The top-view of the super-coiled segment shows a dual half-circle form. There are experimental evidences for such a type of formation in electron micrographs. According to this model, the widely accepted sterically hidrance model on association of actin and myosin can be neglected. One of the main roles of calcium is to make the thin filament segment flexible enough for the association.
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PMID:Contraction due to bimetallic, short-lived super-coiling in the helical, double stranded filaments of striated muscle. 159 59

In a relaxed muscle fiber at low ionic strength, the cross-bridges may well be in states comparable to the one that precedes the cross-bridge power stroke (Schoenberg, M. 1988. Adv. Exp. Med. Biol. 226:189-202). Using electron paramagnetic resonance (EPR) and (saturation transfer) electron paramagnetic resonance (ST-EPR) techniques on fibers labeled with maleimide spin label, under low ionic strength conditions designed to produce a majority of weakly-attached heads, we have established that (a) relaxed labeled fibers show a speed dependence of chord stiffness identical to that of unlabeled, relaxed fibers, suggesting similar rapid dissociation and reassociation of cross-bridges; (b) the attached relaxed heads at low ionic strength are nearly as disordered as in relaxation at physiological ionic strength where most of the heads are detached from actin; and (c) the microsecond rotational mobility of the relaxed heads was only slightly restricted compared to normal ionic strength, implying great motional freedom despite attachment. The differences in head mobility between low and normal ionic strength scale with filament overlap and are thus due to acto-myosin interactions. The spectra can be modeled in terms of two populations: one identical to relaxed heads at normal ionic strength (83%), the other representing a more oriented population of heads (17%). The spectrum of the latter is centered at approximately the same angle as the spectrum in rigor but exhibits larger (40 degrees) axial probe disorder with respect to the fiber axis. Alternatively, assuming that the chord stiffness is proportional to the fraction of attached crossbridges, the attached fraction must be even more disordered than 400, with rotational mobility nearly as great as for detached cross-bridges.
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PMID:Orientational disorder and motion of weakly attached cross-bridges. 165 30


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