Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Chapter VI. BIOCHEMISTRY OF PHYSIOLOGICAL FUNCTIONS AND SPECIALIZED TISSUES

CHAPTER 32. BIOCHEMISTRY OF MUSCLES AND MUSCLE CONTRACTION

32.2. MOLECULAR MECHANISMS OF MUSCLE CONTRACTION

MODERN CONCEPTS OF Muscle contraction mechanisms are based on the sliding filament model proposed by H. Huxley and other researchers

(slide) past one another (H.E. Huxley, J. Hanson, A.F. Huxley, R. Niedergerke, 1954). The main postulates of this model, confirmed by biochemical, biophysical, and electron microscopic studies, are as follows:

- thick (Myosin) and thin (Actin) filaments of myofibrils do not change their length During muscle contraction;

- during muscle contraction, the overall length of the sarcomere decreases due to the sliding and overlapping of thick and thin filaments toward each other;

- contractile force is generated through the active interaction of one type of filament with another, adjacent type of filament.

A diagram illustrating the relative movement of thick and thin filaments of the sarcomere during muscle contraction is shown in Fig. 32.7.

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Fig. 32.7. Model of relative filament displacement in the sarcomere (after H.E. Huxley et al.).

It has also been established that muscle contraction, based on the movement of thick and thin filaments, requires the participation of ATP; the cyclic conversion of ATP into ADP is a prerequisite for both muscle contraction and relaxation.

The Hydrolysis of ATP to ADP and P_H is carried out due to the ATPase activity of the globular S1 myosin heads. The presence of ATPase activity in myosin was first discovered in 1939 by Russian scientists V.A. Engelhardt and M.N. Ljubimova.

The ATP-dependent interaction of actin with myosin, which leads to the relative Displacement of the thin and thick filaments of the sarcomere, occurs as follows (Fig. 32.8):

Fig. 32.8. Scheme of the MOLECULAR MECHANISMS OF muscle contraction (after L. Stryer, 1995, with modifications).

A. In a resting muscle, the S1 myosin heads are not attached to actin filaments. The products of ATP hydrolysis (ADP and P_H) are bound to myosin.

B. Upon muscle excitation, the S1 heads shift toward the thin filaments and bind to actin strands (G-subunits). P_H is released from the complex with myosin.

C. The release of ADP from the complex with myosin is accompanied by a conformational shift in the spatial arrangement of the actin-bound S1 HEAD (A change in the angle between the head and the myofibril axis from 90° to 45°). The change in the spatial orientation of the S1 myosin head relative to the actin strand leads to tension development and the movement of the thin filament relative to the thick one by approximately 100 Å (10 nm) toward the center of the sarcomere.

D. Interaction of the actin-myosin complex with an ATP molecule results in the dissociation of the bond between Actin and myosin. The S1 head detaches from the thin filament once again.

E. The released ATP is hydrolyzed to ADP and P_H due to the ATPase activity of the free myosin heads. The hydrolysis products reassociate with actin. Actin and myosin filaments are ready for a new cycle of interaction and movement.

Regulation of Skeletal Muscle Contraction

The General scheme of muscle contraction, which consists of the mutual displacement of actin and myosin filaments, applies to all muscle types. At the same time, the Biochemical Mechanisms of pathway activation and The regulation of contraction and relaxation differ significantly between skeletal and cardiac Muscles on the one hand, and smooth muscle on the other.

Initiation of muscle contraction is a process triggered by the generation of an Action Potential on the sarcolemma As a result of a chemical signal arriving from the Neuromuscular Junction (for example, upon the release of acetylcholine by a cholinergic neuron and the interaction of the neurotransmitter with a Choline receptor localized in the sarcolemma).

The main biochemical regulator of muscle contraction and relaxation is the change in the cytosolic concentration of Ca²⁺ ions, which at rest (relaxation) is about 10^-8-10^-7 mol/L. The Propagation of the action potential from the sarcolemma to the T-system tubules, which contact the sarcoplasmic reticulum membranes, triggers the release of Ca²⁺ from the SR tubules that act as Ca²⁺ stores in myocytes (in complex with the protein sequestrin). As a result of these processes, the Ca²⁺ concentration in the sarcoplasm reaches 10^-5 mol/L, which initiates the molecular events underlying muscle contraction.

The Tropomyosin-Troponin System as a Regulator of Contraction

The interaction between myosin heads and actin depends on the spatial arrangement of tropomyosin within the thin (actin) filaments. The spatial movement of tropomyosin molecules, which sterically exposes or blocks the binding sites of the myosin S1 heads on the G-actin subunits, can occur via the mechanism schematically shown in Fig. 32.9.

Fig. 32.9. Spatial displacement of tropomyosin (Tm) molecules affecting the potential interaction of myosin S1 heads with actin (A) (cross-sectional view).

In turn, conformational shifts in tropomyosin molecules are triggered by conformational changes within the troponin system induced by fluctuations in Ca²⁺ concentration.

An increase in free Ca²⁺ concentration leads to the activation of TnC, the calcium-dependent component of the troponin system. Through a conformational change, TnC transmits a chemical signal to the other troponin components, TnI and TnT, which regulate the spatial position of tropomyosin. As a result of these molecular events, tropomyosin uncovers the interaction sites between actin and myosin S1 heads, initiating the myofibrillar contraction cycle.

The sequence of chemical signaling events leading to skeletal muscle contraction can be represented as follows:

The decrease in Ca²⁺ concentration in the sarcoplasm occurs due to its reuptake into the sarcoplasmic reticulum tubules via the calcium pump, specifically the SR membrane Ca²⁺-ATPase. Under these conditions, the activation of the troponin complex is suppressed, and tropomyosin shifts into a position that blocks the interaction between myosin heads and actin filaments. The muscle transitions into a relaxed state.

The ATP-ADP Cycle in Contraction Regulation

As follows from the mechanism discussed above, a prerequisite for the muscle's readiness to contract is the ATPase hydrolysis of ATP, which supplies ADP and P_i. Only in complex with ADP and P_i are the myosin S1 heads ready for contraction (states A and E in Fig. 32.8) and "awaiting" a chemical signal to interact with actin filaments.

On the other hand, the dissociation of the bond between myosin and actin filaments (i.e., the return of the muscle to a relaxed state) depends on the presence of ATP, which binds to the myosin S1 heads and drives the muscle into relaxation (stages C-D). When ATP concentration in myocytes drops (due to impaired bioenergetic processes or Hypoxia), the vast majority of myosin S1 heads remain bound to actin, leading to muscle rigidity, the extreme manifestation of which is rigor mortis.

Smooth Muscle Contraction

The initiation of contraction in smooth muscles is also triggered by calcium; however, the mechanisms by which it affects the actin-myosin system differ significantly from those discussed above.

The Regulation of the contraction-relaxation cycle in smooth muscles is achieved through the reversible phosphorylation and dephosphorylation of the regulatory light chains of myosin molecules.

Myosin phosphorylation in smooth muscles is mediated by a Ca²⁺-dependent enzyme, myosin light chain kinase (MLCK) (utilizing high-energy ATP phosphates), whereas dephosphorylation is catalyzed by myosin light chain phosphatase.

The biochemical sequence of reactions:

1. Increase in intracellular Ca²⁺ concentration (due to influx from the extracellular space and release from cellular stores).

2. Interaction of Ca²⁺ with calmodulin (CaM) (forming the CaM-4Ca²⁺ complex).

3. Activation of MLCK by the CaM-4Ca²⁺ complex.

4. Phosphorylation of the light chains in the myosin molecule heads (p-chains). Upon phosphorylation of the p-chains, the myosin heads acquire The ability to interact with actin.

5. Binding of myosin heads to actin molecules in thin filaments, triggering the muscle contraction cycle.

Smooth muscle relaxation occurs under conditions of decreased Ca²⁺ concentration, which halts the activation mechanism of MLCK; dephosphorylation of the light chains shifts the myosin heads into a molecular state where they are unable to interact with actin.