Mechanism of Skeletal Muscle Contraction

The sliding filament theory: It is well accepted that this is the basic mechanism for muscle contraction. Two groups in England, A.F. Huxley and Niedergerke (1954), and H.E. Huxley and Hanson (1954) are the founders of the theory. Their classical experiments are shown in Figures ME1 and ME 2:

Fig. ME1 shows a living frog muscle fiber under the interference microscope. A bands appear dark, I bands are light. The length of the sarcomeres, A and I bands were measured on densitometer tracings. The fiber was stimulated electrically and it was allowed to shorten. On the left side for each frame two numbers are given. The upper numbers indicate the sarcomere length, which in successive times during contraction decreased from 3.10 to 2.93 to 2.70 to 2.37m . The lower numbers indicate A band length, 1.43, 1.45, 1.50, and 1.48 m , that means, it was unchanged during contraction.

Fig. ME2 shows the pictures of glycerol extracted psoas fibrils under phase contrast microscope. A bands are dark, I bands are light, in the middle of I bands the Z lines are seen. Four sarcomeres of one fibril are pictured during ATP induced contraction. A bands did not change in length, but the I bands shortened, in the last frame the I bands disappeared.

Fig. ME1. Changes in sarcomere length and in I band length during contraction of an electrically stimulated frog fiber. (From A.F. Huxley and Niedergerke, 1954).

Fig. ME2. Changes in sarcomere length and in I band length during contraction of a glycerol-extracted fibril contracted by ATP. (From H.E. Huxley and Hanson, 1954).

Further experimentation revealed that during contraction the length of the actin containing thin filaments and the length of the myosin containing thick filaments remain constant. Thus, during contraction the length of the sarcomere and I band decrease, the overlap between thick and thin filaments increase, the lengths of the thick and thin filaments remains unchanged. Consequently, the filaments must slide past each other.

Length-tension relationship: The physiological interpretation of the sliding filament theory was tested by measuring the tension of a single muscle fiber at different sarcomere length (Gordon et al., 1966). Figure ME3 illustrates the experiment. Maximum tension was obtained at rest length, between 2.0-2.25 m , when all crossbridges were in the overlap region between thick and thin filaments. When the muscle fiber was stretched so that the sarcomere length increased from 2.25 to 3.675 m and consequently the number of crossbridges in the overlap region decreased from maximum to zero, the tension fell from 100% to 0.

The crossbridges are uniformly distributed along the thick filaments with the exception of a short bare zone in the middle. The crossbridges seem to be identical and are the site of the interaction between thick and thin filaments. The tension is the algebraic sum of the tension produced at each individual site. At or above rest length the tension is directly proportional to the number of crossbridges in the overlap region between thick and thin filaments.

Below rest length, when the thin filaments meet in the center of A band or they start to interact with the oppositely directed crossbridge sites past the bare zone (in the middle of the sarcomere), tension drops off.

 

Fig. ME3. Length-tension relationship of a single frog semitendinosus muscle fiber. (From Gordon et al., 1966). The numbers 1 through 6 on the length tension curve correspond to the numbers on the schematic diagram of thick and thin filament arrangement. In this way the relationship between thick and thin filaments can be compared to the tension at various sarcomere length.

 

Crossbridge cycle and its relation to actomyosin ATPase: A scheme for the coupling of ATP hydrolysis to the crossbridge cycle is shown in Fig. ME4. The following major steps are involved:

  1. ATP dissociates actomyosin into actin and myosin; i.e. the thick filaments will be detached from the thin filaments. ATP binds to the myosin head in the thick filaments.
  2. ATP is hydrolyzed by myosin; the products ADP and Pi are bound to myosin. The energy released by the splitting of ATP is stored in the myosin molecule. The myosin.ADP.Pi complex is a high-energy state; this is the predominant state at rest.
  3. Upon muscle stimulation, the inhibition of actin-myosin interaction, imposed by the regulatory proteins, is lifted and consequently the myosin with bound ADP and Pi attaches to actin. It is believed that the angle of crossbridge attachment is 90o.
  4. The actin-myosin interaction triggers the sequential release of Pi and ADP from the myosin head, resulting in the working stroke. It is thought that the energy stored in the myosin molecule brings about a conformational change in the crossbridge tilting the angle from 90o to 45o. This tilting pulls the actin filament about 10 nm toward the center of the sarcomere, while the energy stored in myosin is utilized.

With a new ATP a new cycle may begin and the cycling may continue till the regulatory mechanism stops the interaction of actin and myosin. As shown in Fig. ME4, ATP is needed for step 1 that is for the detachment of myosin from actin. In case of ATP depletion, the cycle is arrested. When actin and myosin are permanently bound in the absence of ATP, the muscle becomes rigid. This state is called rigor mortis.

Fig. ME4. Crossbridge cycle and its relation to actomyosin ATPase. (From Voet and Voet, 1990).

Summary of Events in Skeletal Muscle Contraction

Excitation

The sarcolemma is depolarized and the action potential propagates

The action potential spreads inside along the T-tubules

The signal is transmitted from T-tubule to terminal sacs of sarcoplasmic reticulum

Calcium is released from sarcoplasmic reticulum into sarcoplasm

Contraction

Calcium binds to troponin

Cooperative conformational changes take place in troponin-tropomyosin system

The inhibition of actin and myosin interaction is released

Crossbridges of myosin filaments are attached to actin filaments

Tension is exerted, and/or the muscle shortens by the sliding filament mechanism

Relaxation

Calcium is pumped into sarcoplasmic reticulum

Crossbridges are detached from the thin filaments

Troponin-tropomyosin regulated inhibition of actin and myosin interaction is restored

Active tension disappears and the rest length is restored

 

References

Gordon, A.M., Huxley, A.F., and Julian, F.J. (1966). The variation in isometric tension with sarcomere length in vertebrate muscle fibres. J. Physiol., 184, 170-192.

Huxley, A.F. and Niedergerke, R. (1954). Structural changes in muscle during contraction. Interference microscopy of living muscle fibres. Nature, 173, 971-973.

Huxley, H.E. and Hanson, J. (1954). Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature, 173, 973-976.

Voet, D. and Voet, J.G. (1990). Biochemistry. John Wiley and Sons.


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