Biological Chemistry - Berezov, T. T., Korovkin, B. F. 1998

Muscle Tissue
Functional Biochemistry of Muscles
Mechanism of Muscle Contraction

Let us examine the current understanding of the mechanism underlying the alternating contraction and relaxation of Muscles. It is now widely accepted that the biochemical cycle of Muscle contraction consists of 5 stages (Fig. 20.8):

1) the Myosin HEAD can hydrolyze ATP to ADP and H₃PO₄ (P_i), yet it does not release the Hydrolysis products. Therefore, this process is stoichiometric rather than catalytic in nature (see Fig. 20.8, a);

2) the myosin head, loaded with ADP and H₃PO₄, is free to rotate over a wide angle and (upon reaching the proper orientation) binds to F-Actin, forming an angle of approximately 90° with the fibril axis (see Fig. 22.8, b);

3) this interaction triggers the release of ADP and H₃PO₄ from the actin-myosin complex. Because the Actomyosin bond has its lowest energy at a 45° angle, the angle between the myosin head and the fibril axis shifts from 90° to roughly 45°, propelling the actin filament (by 10–15 nm) toward the center of the sarcomere (see Fig. 20.8, c);

4) a fresh ATP molecule binds to the myosin–F-actin complex (see Fig. 20.8, d);

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Fig. 20.8. Biochemical cycle of muscle contraction. Explanations are provided in the text.

5) the myosin–ATP complex exhibits a low affinity for actin, causing the myosin (ATP) head to dissociate from F-actin. This final stage constitutes muscle relaxation proper, which is strictly dependent on ATP binding to the actin-myosin complex (see Fig. 20.8, e). The cycle then repeats.

Regulation of Muscle contraction and relaxation. The contraction of any muscle follows the general mechanism described previously. Although the muscle fibers of different Organs may feature distinct molecular mechanisms regulating contraction and relaxation, Ca²⁺ ions consistently play a key regulatory role. It has been established that myofibrils are capable of interacting with ATP and contracting in its presence only when specific concentrations of Calcium Ions are present in the medium*. Maximum contractile activity is observed at a Ca²⁺ ion concentration of approximately 10^-6–10^-5 M. When the concentration drops to 10^-7 M or lower, muscle fibers lose their ability to shorten and develop tension in the presence of ATP.

* The molecular structures of smooth muscles are quite similar to those of striated muscles, but the arrangement of sarcomeres within them does not produce the characteristic striated pattern typical of striated muscle. Like skeletal muscles, smooth muscles contain $\alpha$-actinin and Tropomyosin molecules, but they lack the troponin system. Nevertheless, the contraction of smooth muscles, much like that of striated muscles, is regulated by Ca²⁺ ions.

According to current understanding, in a resting muscle (within both myofibrils and the intermyofibrillar space), the concentration of Ca²⁺ ions is maintained below the threshold level through their binding by the structures (tubules and vesicles) of the sarcoplasmic reticulum and the so-called T-system, involving a specialized Ca²⁺-binding protein known as calsequestrin, which is an integral component of these structures.

The binding of Ca²⁺ ions by the intricate network of tubules and cisternae of the sarcoplasmic reticulum is not a simple adsorption process. It is an active physiological mechanism driven by The energy released during the hydrolysis of ATP by the Ca²⁺-dependent ATPase of the sarcoplasmic reticulum*. A rather unique phenomenon is observed here: The rate of Ca²⁺ ion pumping out of the intermyofibrillar space is stimulated by these very ions. Overall, this mechanism is referred to as the "calcium pump," by analogy with the well-known sodium pump in physiology.

The ability of a living muscle to remain relaxed in the presence of a sufficiently high ATP concentration is explained by the calcium pump lowering the concentration of Ca²⁺ ions in the medium surrounding the myofibrils below the threshold required for ATPase activity and the contractility of the fiber's actomyosin structures. The rapid contraction of a muscle fiber upon stimulation by a nerve (or an electric current) results from a sudden change in membrane permeability, leading to the release of a certain amount of Ca²⁺ ions from the cisternae and tubules of the sarcoplasmic reticulum and T-system into the sarcoplasm.

As noted, the "sensitivity" of the actomyosin system to Ca²⁺ ions (i.e., the loss of actomyosin's ability to split ATP and contract in the presence of ATP when the Ca²⁺ ion concentration drops to 10^-7 M) is due to the presence of the troponin-tropomyosin protein complex located on the F-actin filaments within the contractile system. Within this complex, Ca²⁺ ions bind specifically to troponin. This binding induces Conformational Changes in the troponin molecule, which presumably shift the entire troponin-tropomyosin rod and unblock the active sites on actin that interact with myosin to form the contractile complex and active Mg²⁺-ATPase.

According to E. Huxley, temporary cross-bridges, which represent the "heads" of myosin molecules, play a crucial role in driving actin filaments along myosin filaments. Thus, the greater the number of cross-bridges attached to the actin filaments at any given moment, the greater the force of muscle contraction.

Finally, when excitation ceases and the Ca²⁺ ion concentration in the sarcoplasm decreases (via the calcium pump), the attachment-release cycles stop, meaning that the myosin filament "heads" cease to attach to the actin filaments. In the presence of ATP, the muscle relaxes and returns to its initial length. If the supply of ATP ceases (due to anoxia, poisoning by respiratory toxins, or death), the muscle enters a state of rigor. In this state, almost all cross-bridges of the thick (myosin) filaments are attached to the thin actin filaments, resulting in complete muscle rigidity.

* There is yet another component of the sarcoplasmic reticulum's Ca²⁺-regulating system: an ionophore, which is a proteolipid extracted from the reticulum known to accelerate the action of the ATPase pump.