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Biomedical subjects

A F Huxley

Publications and source records attributed to A F Huxley.

At least 19 recordsLinked to original sources
PubMed2002

Hodgkin and the action potential 1935-1952.

It is naturally very gratifying that the Editors of The Journal of Physiology have decided to make available online a paper that Alan Hodgkin and I published 50 years ago (Hodgkin & Huxley, 1952). This was the final paper in the series on the voltage clamp experiments by us and Bernard Katz. In this note, I will set out the background against which this work was done.

Action Potentials↗
PubMed2000

Mechanics and models of the myosin motor.

In striated muscles, shortening comes about by the sliding movement of thick filaments, composed mostly of myosin, relative to thin filaments, composed mostly of actin. This is brought about by cyclic action of 'cross-bridges' composed of the heads of myosin molecules projecting from a thick filament, which attach to an adjacent thin filament, exert force for a limited time and detach, and then repeat this cycle further along the filament. The requisite energy is provided by the hydrolysis of a molecule of adenosine triphosphate to the diphosphate and inorganic phosphate, the steps of this reaction being coupled to mechanical events within the cross-bridge. The nature of these events is discussed. There is good evidence that one of them is a change in the angle of tilt of a 'lever arm' relative to the 'catalytic domain' of the myosin head which binds to the actin filament. It is suggested here that this event is superposed on a slower, temperature-sensitive change in the orientation of the catalytic domain on the actin filament. Many uncertainties remain.

Actins↗
PubMed2000

Cross-bridge action: present views, prospects, and unknowns.

When the sliding filament hypothesis was proposed in 1953-1954, existing evidence showed that (1) contributions to tension were given by active sites uniformly distributed within each zone of filament overlap and (2) each site functioned cyclically. These sites were identified by electron microscopy as cross-bridges between the two filaments, formed of the heads of myosin molecules projecting from a thick filament and attaching to a thin filament. The angle of these cross-bridges was found to be different at rest and in rigor, suggesting that the event causing relative motion of the filaments was a change of the angle of the cross-bridges. At first, it seemed likely that the whole cross-bridge rotated about its attachment to actin, but when the atomic structures of actin and myosin were obtained by X-ray crystallography, a possible hinge was found between the "catalytic domain" which attaches to the actin filament and the "light-chain domain" which appears to act as a lever arm. Two attitudes of the lever arm are now well established, the transition between them being driven by a conformational change coupled to some step in the hydrolysis of ATP, but several recent observations suggest that this is not the whole story: a third attitude has been shown by X-ray crystallography; a non-muscle myosin has been shown to produce its working stroke in two steps; and there are suggestions that an additional displacement of the filaments is produced by a change in the attitude of the catalytic domain on the thin filament.

Animals↗
PubMed1997

Rapid regeneration of power stroke in contracting muscle by attachment of second myosin head.

When Lombardi and colleagues reported the phenomenon of rapid regeneration of the power stroke after a quick release of muscle fibre during a tetanus, they gave an explanation in terms of detachment of cross-bridges and re-attachment further along the thin filament. We show here that the phenomenon can also be explained on assumptions that lead to a majority of myosin molecules being attached by only one head during steady isometric contraction; the other head may then become attached after a quick release and can add its contribution to the early tension recovery after a second release.

Isometric Contraction↗
PubMed1996

Filament compliance and tension transients in muscle.

Huxley and Simmons (1971) proposed an explanation for some striking features in the transient tension response of a tetanized muscle fibre to sudden stretch or release. More recent work has shown that the stiffness of cross-bridges in skeletal muscle is an order of magnitude greater than appeared at that time. On the simplified treatment used in that paper, this would cause serious disagreement with the experimental observations. It is shown here analytically and by computer simulations that these discrepancies disappear when account is taken of (a) the range of positions of myosin molecules relative to attachment sites on the thin filament and (b) the recently-discovered compliance in the thin filaments.

Actin Cytoskeleton↗
PubMed1995

Identification of source of oscillations in apparent sarcomere length measured by laser diffraction.

The most widely used technique for dynamic estimates of sarcomere length in muscle is laser light diffraction. We have identified conditions under which artifactual oscillations can arise in apparent sarcomere length measured by this technique and report methods to reduce the effect. Altringham et al. (1984) first reported that the diffraction angle can exhibit one cycle of oscillation for each sarcomere length displacement of the illuminated portion of the fiber. We find that the amplitude of similar oscillations is strongly dependent on the intensity of light scattered from objects near the fiber and on the spacing between fiber and scatterer. The oscillations can be eliminated by minimizing scattered light and positioning the fiber a few millimeters from sources of scattering. A theoretical description shows that oscillations of this kind are expected from interference of scattered and diffracted light. Interference fringes were observed along the meridian of the pattern, and these moved during translation of either a fiber or a grating. The movement of fringes across the diffraction order shifts the centroid back and forth and, when associated with steady shortening, can give rise to "steps" and "pauses" in apparent striation spacing.

Animals↗
PubMed1994

A program for developing a comprehensive mathematical description of the crossbridge cycle of muscle.

We describe a computer modeling system for determining the changes of force, fraction of attached crossbridges, and crossbridge flux rate through a specifiable transition in response to length changes imposed on a crossbridge model of muscle. The crossbridge cycle is divided into multiple attached and detached states. The rates of transition from one state to another are defined by rate coefficients that can either be constant or vary with the position of the crossbridge relative to the thin-filament attachment site. This scheme leads to a system of differential equations defining the rates of change for the fractions of bridges in each state. Solutions for this system of equations are obtained at specified times during and after a length change using a method for systems with widely varying time constants (C. W. Gear, 1971, Numerical Initial Value Problems in Ordinary Differential Equations, Prentice-Hall, Englewood Cliffs, NJ). Crossbridges are divided into discrete populations that differ both in their axial displacement with respect to thin filament attachment sites and with respect to the twist of the actin helix. Separate solutions are made for the individual populations and are then averaged to obtain the ensemble response. Force is determined as the sum of the product of the force associated with each state multiplied by the fraction of bridges in that state. A measure of metabolic rate is determined as the net flux through one of the crossbridge transitions. When the force-extension characteristics of the individual crossbridges are linear and the filaments are noncompliant the fraction of attached bridges is equivalent to sarcomere stiffness. To illustrate the operation of the program, we also describe here some results obtained with a simplified scheme.

Actins↗
PubMed1986

Tension transients during the rise of tetanic tension in frog muscle fibres.

Tension transients were recorded from fibres isolated from the tibialis anterior muscle of the frog during the rise of tetanic tension at 0.8-2.5 degrees C. The length of a central segment of the fibre was controlled by feed-back from a spot-follower device. Length steps complete within 0.2 ms were applied at one end of the fibre, and tension changes were recorded at the other end with a transducer having a natural frequency of 10.8 kHz. The tension transients measured during the rise of force showed the four phases characteristic of transients recorded during the plateau of a tetanus and during shortening. The extreme tension change reached during a length change was smaller for a given size of step during the rise of tension than at the plateau, but by less than in proportion to the developed force, suggesting that stiffness increases earlier than tension. Stiffness changes were further assessed by matching the tension records from one fibre with the responses of an analogue circuit (delay line) representing the mechanical properties of the fibre and force transducer. Stiffness derived from these comparisons varied in approximately the same proportion as stiffness assessed from the extreme tension change. During the rise of tension, there was a roughly constant lag of tension behind stiffness, ranging from 11 to 16 ms in different fibres. Steps applied during the latent period showed a lag of about 10 ms from the first increase of stiffness to the first appearance of tension. The partial recovery of tension immediately following the step, phase 2, was faster at the low tension levels early in the tetanus. The intermediate level, T2, to which tension recovers during phase 2 scaled in approximate proportion to the tension level immediately preceding the step. This result is unlike the relative decrease in T2 levels we have recently described for steps applied during steady shortening, and suggests that the increased stiffness-tension ratio seen during the rise of tetanic force is not due to shortening within the sarcomeres. The results can be explained if the attachment of cross-bridges in the rising phase takes place in two steps, the initial state of attachment resulting in the production of little or no tension. Several such schemes are considered.

Animals↗
PubMed1985

Tension transients during steady shortening of frog muscle fibres.

Single intact fibres from frog muscle at 0-1 degrees C were stimulated to produce isometric tetani at a sarcomere length of about 2.25 micron, using a spot-follower apparatus to control the length of the central part of a fibre. When the plateau of the tetanus was reached the fibre was forced to shorten by applying a step and ramp length change in an approximation to an isotonic release. When tension had reached a steady level, Ti, during shortening, tension transients were elicited by applying step changes of length, complete within 0.2 ms, ranging from a stretch of 1.5 nm per half-sarcomere to a release of 6 nm per half-sarcomere. The tension transients recorded during shortening were qualitatively similar to those previously recorded in isometric tetani. There were four phases: phase 1, the change of tension during the step; phase 2, a rapid partial recovery of tension; phase 3, a delay or reversal of recovery; phase 4, a slower recovery of tension to the level before the step was applied. Measurements were made of the extreme tension, T1, attained during a step, and the level, T2, to which tension recovers in phase 2. The excursion of tension, [T1-Ti], during a small step of given size, fell with increase of shortening velocity, reaching about 40% of the isometric value near the maximum velocity of shortening. T2 fell as shortening velocity was increased and the fraction of steady tension recovered, T2/Ti, also decreased, so that the proportion of tension recovery in phase 4 increased. All the recovery phases became progressively more rapid with increase of shortening velocity. The early tension response was matched with a delay-line simulator so as to estimate the value of the instantaneous stiffness. Stiffness during shortening was found to decrease approximately linearly with tension, reaching about 35% of the isometric value as tension approached zero. It was impossible to match the early tension response in a rapidly shortening fibre without assuming decreased stiffness. The decline of stiffness is interpreted as due largely to reduced number of attached cross-bridges, but quantitative estimates would be affected by possible filament compliance and non-linearity of cross-bridge stiffness. The decrease in T2 also suggests fewer cross-bridges are attached as shortening velocity increases, but uncertainties about the processes determining phase 2 during shortening do not permit a precise estimate of stiffness to be made.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Structural studies of the waves in striated muscle fibres shortened passively below their slack length.

Isolated skeletal muscle fibres of Rana pipiens were shortened below their slack length by longitudinal compression in a gelatine block, and examined by light and electron microscopy. Waves appeared sharply when the striation spacing (S) reached a critical value (about 2 microns) and increased in height with further compression down to S = 1.6 microns while the resting band pattern was maintained. The waves were plane, helical or irregular, with wave lengths of 5-15 striations. The Z lines usually ran perpendicular to the direction of the myofibrils to form wedge-shaped sarcomeres. The bending occurred mainly in the I band. The thin filaments ran stiffly for about 30 nm from the Z line and then bent toward the A band. The thick filaments bent very slightly, particularly at their tips. The edges of the A band were indistinct, and there were no dense lines at the A-I junction. The appearance of the individual sarcomeres resembled those in relaxed myofibrils at slack length, with no Cm bands. The H zone was only seen occasionally in the slack and wavy fibres examined. In very thin sections the individual thin filaments were seen to end in the pseudo-H zone, and not to cross the M line. There was a single array of not more than six thin filaments round each thick one in transverse sections of the M-line region. These observations suggest that the narrowing of the bands observed in fresh wavy fibres is due mainly to the obliquity of the myofibrils, and that the sarcomere length measured parallel to their axis is longer than the striation spacing. The relationship between sarcomere length and the length of the thin-filament complex is discussed.

Animals↗