Molecular Mechanisms of Contraction

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The term contraction, as used in muscle physiology, does not necessarily mean "shortening"; rather it refers only to the turning on of the force-generating sites— the cross bridges—in a muscle fiber. Following contraction, the mechanisms that initiate force generation are turned off, and tension declines, allowing relaxation of the muscle fiber.

Sliding-Filament Mechanism

When force generation produces shortening of a skeletal-muscle fiber, the overlapping thick and thin

Vander et al.: Human I II. Biological Control I 11. Muscle I I © The McGraw-Hill

Physiology: The Systems Companies, 2001 Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems

Muscle Contraction Mechanism

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FIGURE 11-5

(a) Numerous myofibrils in a single skeletal-muscle fiber (arrows in upper right corner indicate mitochondria between the myofibrils). (b) High magnification of a sarcomere within a myofibril (arrow at the right of A band indicates end of a thick filament). (c) Arrangement of the thick and thin filaments in the sarcomere shown in b. %

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

II. Biological Control Systems

11. Muscle

© The McGraw-Hill Companies, 2001

Muscle CHAPTER ELEVEN

Muscle CHAPTER ELEVEN

(b) Thick filament

Thick Thin filament filament

Thin filament

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FIGURE 11-6

(a) Electron micrograph of a cross section through several myofibrils in a single skeletal-muscle fiber.

From H. E. Huxley, J. Mol. Biol., 37:507-520 (1968).

(b) Hexagonal arrangements of the thick and thin filaments in the overlap region in a single myofibril. Six thin filaments surround each thick filament, and three thick filaments surround each thin filament.

M line

M line

Hexagonal Arrangement Filaments

H zone

FIGURE 11-7

High-magnification electron micrograph in the filament-overlap region near the middle of a sarcomere. Cross bridges between the thick and thin filaments can be seen at regular intervals along the filaments.

From H. E. Huxley and J. Hanson, in G. H. Bourne (ed.), "The Structure and Function of Muscle," Vol. 1, Academic Press, New York, I960.

H zone

FIGURE 11-7

High-magnification electron micrograph in the filament-overlap region near the middle of a sarcomere. Cross bridges between the thick and thin filaments can be seen at regular intervals along the filaments.

From H. E. Huxley and J. Hanson, in G. H. Bourne (ed.), "The Structure and Function of Muscle," Vol. 1, Academic Press, New York, I960.

Vander et al.: Human I II. Biological Control I 11. Muscle I I © The McGraw-Hill

Physiology: The Systems Companies, 2001 Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems filaments in each sarcomere move past each other, propelled by movements of the cross bridges. During this shortening of the sarcomeres, there is no change in the lengths of either the thick or thin filaments (Figure 11-8). This is known as the sliding-filament mechanism of muscle contraction.

During shortening, each cross bridge attached to a thin filament moves in an arc much like an oar on a boat. This swiveling motion of many cross bridges forces the thin filaments at either end of the A band toward the center of the sarcomere, thereby shortening the sarcomere (Figure 11-9). One stroke of a cross bridge produces only a very small movement of a thin filament relative to a thick filament. As long as a muscle fiber remains "turned on," however, each cross bridge repeats its swiveling motion many times, resulting in large displacements of the filaments.

Let us look more closely at these events. A muscle fiber's ability to generate force and movement depends on the interactions of the two so-called contractile proteins—myosin in the thick filaments and actin in the thin filaments—and energy provided by ATP.

An actin molecule is a globular protein composed of a single polypeptide that polymerizes with other actins to form two intertwined helical chains (Figure 11-10) that make up the core of a thin filament. Each actin molecule contains a binding site for myosin. The myosin molecule, on the other hand, is composed of two large polypeptide heavy chains and four smaller light chains. These polypeptides combine to form a molecule that consists of two globular heads (containing heavy and light chains) and a long tail formed by the two intertwined heavy chains (Figure 11-11b). The tail of each myosin molecule lies along the axis of the thick filament, and the two globular heads extend out to the sides, forming the cross bridges. Each globular head contains two binding sites, one for actin and one for ATP. The ATP binding site also serves as an enzyme—an ATPase that hydrolyzes the bound ATP.

The myosin molecules in the two ends of each thick filament are oriented in opposite directions, such that their tail ends are directed toward the center of the filament (Figure 11-11a). Because of this arrangement, the power strokes of the cross bridges move the attached thin filaments at the two ends of the sarcomere toward the center during shortening (see Figure 11-9).

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FIGURE 11-8

The sliding of thick filaments past overlapping thin filaments produces shortening with no change in thick or thin filament length. The I band and H zone have, however, decreased. % rrâ

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

II. Biological Control Systems

11. Muscle

© The McGraw-Hill Companies, 2001

Muscle CHAPTER ELEVEN

Muscle CHAPTER ELEVEN

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Z line

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FIGURE 11-9

Cross bridges in the thick filaments bind to actin in the thin filaments and undergo a conformational change that propels the thin filaments toward the center of a sarcomere. (Only 2 of the approximately 200 cross bridges in each thick filament are shown.)

Thin filament

Thick filament

FIGURE 11-9

Cross bridges in the thick filaments bind to actin in the thin filaments and undergo a conformational change that propels the thin filaments toward the center of a sarcomere. (Only 2 of the approximately 200 cross bridges in each thick filament are shown.)

Actin molecule

Thin filament

FIGURE 11-10

Two intertwined helical chains of actin molecules form the primary structure of the thin filaments.

FIGURE 11-11

(a) The heavy chains of myosin molecules form the core of a thick filament. The myosin molecules are oriented in opposite directions in either half of a thick filament. (b) Structure of a myosin molecule. The two globular heads of each myosin molecule extend from the sides of a thick filament forming a cross bridge.

FIGURE 11-11

(a) The heavy chains of myosin molecules form the core of a thick filament. The myosin molecules are oriented in opposite directions in either half of a thick filament. (b) Structure of a myosin molecule. The two globular heads of each myosin molecule extend from the sides of a thick filament forming a cross bridge.

Vander et al.: Human I II. Biological Control I 11. Muscle I I © The McGraw-Hill

Physiology: The Systems Companies, 2001 Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems

The sequence of events that occurs between the time a cross bridge binds to a thin filament, moves, and then is set to repeat the process is known as a cross-bridge cycle. Each cycle consists of four steps:

(1) attachment of the cross bridge to a thin filament,

(2) movement of the cross bridge, producing tension in the thin filament, (3) detachment of the cross bridge from the thin filament, and (4) energizing the cross bridge so that it can again attach to a thin filament and repeat the cycle. Each cross bridge undergoes its own cycle of movement independently of the other cross bridges, and at any one instant during contraction only a portion of the cross bridges overlapping a thin filament are attached to the thin filaments and producing tension, while others are in a detached portion of their cycle.

The chemical and physical events during the four steps of a cross-bridge cycle are illustrated in Figure 11-12. At the conclusion (step 4) of the preceding cycle, the ATP bound to myosin is split, releasing chemical energy which results in a conformational change in the cross bridge. This produces an energized form of myosin (M*) to which the products of ATP hydrolysis, ADP and inorganic phosphate (Pj), are still bound. This storage of energy in myosin is analogous to the storage of potential energy in a stretched spring.

ATP hydrolysis

Cross bridge binds to actin

Thin filament (actin, A)

Energized — cross bridge

Thick filament M line (myosin, M)

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Hydrolysis of ATP energizes cross bridge

Cross bridge moves

Thick filament M line (myosin, M)

Z line

Hydrolysis of ATP energizes cross bridge

Crossbridge Huxley

Cross bridge moves

ATP binds to myosin, causing cross bridge to detach

FIGURE 11-12

Chemical and mechanical changes during the four stages of a cross-bridge cycle. In a resting muscle fiber, contraction begins with the binding of a cross bridge to actin in a thin filament—step 1. (M* represents an energized myosin cross bridge.) %

ATP binds to myosin, causing cross bridge to detach

FIGURE 11-12

Chemical and mechanical changes during the four stages of a cross-bridge cycle. In a resting muscle fiber, contraction begins with the binding of a cross bridge to actin in a thin filament—step 1. (M* represents an energized myosin cross bridge.) %

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Muscle CHAPTER ELEVEN

Muscle CHAPTER ELEVEN

A new cross-bridge cycle begins with the binding of an energized myosin cross bridge to actin (A) in a thin filament (step 1):

Step 1

Actin binding

The binding of energized myosin to actin triggers the release of the strained conformation of the energized bridge, which produces the movement of the bound cross bridge (step 2) and the release of ADP and

Cross-bridge movement

This sequence of energy storage and release by myosin is analogous to the operation of a mousetrap: Energy is stored in the trap by cocking the spring (ATP hydrolysis) and released after springing the trap (binding to actin).

During the cross-bridge movement, myosin is bound very firmly to actin, and this linkage must be broken in order to allow the cross bridge to be reenergized and repeat the cycle. The binding of a molecule of ATP to myosin breaks the link between actin and myosin (step 3):

Step 3

Cross-bridge dissociation from actin

The dissociation of actin and myosin by ATP is an example of allosteric regulation of protein activity. The binding of ATP at one site on myosin decreases myosin's affinity for actin bound at another site. Thus, ATP is acting as a modulator molecule controlling the binding of actin to myosin. Note that ATP is not split in this step; that is, it is not acting as an energy source but only as a modulator molecule that produces an allosteric modulation of the myosin head that weakens the binding of myosin to actin.

Then, following the dissociation of actin and myosin, the ATP bound to myosin is split (step 4), thereby re-forming the energized state of myosin, which can now reattach to a new site on the actin filament and repeat the cycle. Note that the release of energy by the hydrolysis of ATP (step 4) and the movement of the cross bridge (step 2) are not simultaneous events.

To summarize, ATP performs two distinct roles in the cross-bridge cycle: (1) The energy released from ATP hydrolysis ultimately provides the energy for cross-bridge movement, and (2) ATP binding (not hydrolysis) to myosin breaks the link formed between actin and myosin during the cycle, allowing the cycle to be repeated.

The importance of ATP in dissociating actin and myosin during step 3 of a cross-bridge cycle is illustrated by rigor mortis, the stiffening of skeletal muscles that begins several hours after death and is complete after about 12 h. The ATP concentration in cells, including muscle cells, declines after death because the nutrients and oxygen required by the metabolic pathways to form ATP are no longer supplied by the circulation. In the absence of ATP, nonenergized cross bridges can bind to actin, but the subsequent movement of the cross bridge and the breakage of the link between actin and myosin do not occur because these events require ATP. The thick and thin filaments become bound to each other by immobilized cross bridges, producing a rigid condition in which the thick and thin filaments cannot be passively pulled past each other. The stiffness of rigor mortis disappears about 48 to 60 h after death as a result of the disintegration of muscle tissue.

Roles of Troponin, Tropomyosin, and Calcium in Contraction

Since every muscle fiber contains all the ingredients necessary for cross-bridge activity (actin, myosin, and ATP) the question arises: Why are muscles not in a continuous state of contractile activity? The answer is that in a resting muscle fiber, the cross bridges are prevented from interacting with actin by two proteins, troponin and tropomyosin, which, as noted earlier, are located on thin filaments (Figure 11-13).

Tropomyosin is a rod-shaped molecule composed of two intertwined polypeptides with a length approximately equal to that of seven actin molecules. Chains of tropomyosin molecules are arranged end to end along the actin thin filament. These tropomyosin molecules partially cover the myosin-binding site on each actin molecule, thereby preventing the cross bridges from making contact with actin. Each tropomyosin molecule is held in this blocking position by troponin, a smaller, globular protein that is bound to both tropomyosin and actin. One molecule of tro-ponin binds to each molecule of tropomyosin and regulates the access to myosin-binding sites on the seven actin molecules in contact with tropomyosin.

Having described the system that prevents cross-bridge activity and thus keeps a muscle fiber in a resting state, we can now ask: What enables cross bridges to bind to actin and begin cycling? For this to occur, tropomyosin molecules must be moved away from their blocking positions on actin. This happens when calcium binds to specific binding sites on troponin (not tropomyosin). The binding of calcium produces a change in the shape of tro-ponin, which through troponin's linkage to tropomyosin,

PART TWO Biological Control Systems

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems

Troponin

Troponin

Ca2+ binding site

Tropomyosin

Tropomyosin

TrAnnnin

Tropomyosin

TrAnnnin

Cross-bridge binding sites

FIGURE 11-13

(a) Molecule of troponin bound to a molecule of tropomyosin. (b) Two chains of tropomyosin on a thin filament regulate access of cross bridges to binding sites on actin.

Cross-bridge binding sites

FIGURE 11-13

(a) Molecule of troponin bound to a molecule of tropomyosin. (b) Two chains of tropomyosin on a thin filament regulate access of cross bridges to binding sites on actin.

drags tropomyosin away from the myosin-binding site on each actin molecule. Conversely, removal of calcium from troponin reverses the process, turning off contractile activity.

Thus, cytosolic calcium-ion concentration determines the number of troponin sites occupied by calcium, which in turn determines the number of actin sites available for cross-bridge binding. Changes in cy-tosolic calcium concentration are controlled by electrical events in the muscle plasma membrane, which we now discuss.

and thin filaments is very low, about 10~7 mol/L. At this low calcium concentration, very few of the calcium-binding sites on troponin are occupied, and thus cross-bridge activity is blocked by tropomyosin. Following an action potential, there is a rapid increase in cyto-solic calcium concentration, and calcium binds to tro-ponin, removing the blocking effect of tropomyosin and allowing cross-bridge cycling. The source of the increased cytosolic calcium is the sarcoplasmic reticulum within the muscle fiber.

Excitation-Contraction Coupling Excitation-contraction coupling refers to the sequence of events by which an action potential in the plasma membrane of a muscle fiber leads to cross-bridge activity by the mechanisms just described. The skeletal-muscle plasma membrane is an excitable membrane capable of generating and propagating action potentials by mechanisms similar to those described for nerve cells (Chapter 8). An action potential in a skeletal-muscle fiber lasts 1 to 2 ms and is completed before any signs of mechanical activity begin (Figure 11-14). Once begun, the mechanical activity following an action potential may last 100 ms or more. The electrical activity in the plasma membrane does not directly act upon the contractile proteins but instead produces a state of increased cytosolic calcium concentration, which continues to activate the contractile apparatus long after the electrical activity in the membrane has ceased.

In a resting muscle fiber, the concentration of free, ionized calcium in the cytosol surrounding the thick

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Responses

  • Paolo
    Are thick and thin filaments molecules?
    8 years ago
  • zemzem
    What is the correct sequence of events in filament cross bridge cycling?
    8 years ago

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