Regulation of contractile activity is smooth. Regulation of smooth muscle contraction. Stopping smooth muscle contraction Regulating smooth muscle tissue only by the nervous system
General ideas about the structure of various muscles
Many cells have a limited ability to convert chemical energy into mechanical force and movement, but only muscle fibers this process took center stage. The main function of these specialized cells is to generate force and movement, which the body uses to regulate the internal environment and move in external space.
Based on the structure, contractile properties and regulatory mechanisms, three types of muscle tissue are distinguished:
1) skeletal muscles;
2) smooth muscles;
3) heart muscle (myocardium).
Skeletal muscles, as their name suggests, are usually attached to the bones of the skeleton; Thanks to the contractions of these muscles, the position of the skeleton in space is maintained and its movements occur. Contractions occur under the influence of impulses from nerve cells and are usually voluntary.
Figure 4-1 A shows a skeletal muscle fiber (top panel), a cardiac muscle cell (middle panel), and a smooth muscle(the bottom panel). A skeletal muscle cell is called muscle fiber. During embryonic development, each muscle fiber is formed by the fusion of many undifferentiated mononuclear cells (myoblasts) into one cylindrical multinucleated cell. Skeletal muscle differentiation is completed around the time of birth. During the period from infancy to adulthood, the size of differentiated muscle fibers continues to increase, but new fibers are not formed from myoblasts. In an adult, the diameter of muscle fibers reaches 10-100 microns, length - up to 20 cm.
If damage to skeletal muscle fibers occurs in the postnatal period, they cannot be replaced by dividing the remaining fibers, but new fibers are formed from undifferentiated cells, the so-called satellite cells located next to muscle fibers and undergoing differentiation similar to embryonic myoblasts. The potential for the formation of new fibers in skeletal muscle is significant, but after severe damage it is no longer fully restored. Important role in compensation
lost muscle tissue is played by an increase in intact muscle fibers.
In the picture fig. 4-1 A, D also shows the heart muscle (myocardium), which ensures the functioning of the heart.
Layers of smooth muscle are found in the walls of the hollow internal organs and tubular formations: stomach, intestines, bladder, uterus, blood vessels, bronchi. As a result of contractions of smooth muscles, the contents of hollow organs are pushed through, and the flow of fluid in vessels and ducts is regulated by changing their diameter. Small bunches smoothly muscle cells are also found in the skin near the hair follicles and in the iris of the eye. Smooth muscle contractions are controlled by the autonomic nervous system, hormones, autocrine/paracrine factors, and other local chemical signals. Some smooth muscles contract spontaneously even in the absence of signals. Unlike skeletal muscles, smooth muscles do not have voluntary regulation.
Despite the significant differences between these three types of muscles, they have a similar mechanism for generating force. Skeletal muscle will be examined first, followed by smooth muscle. The cardiac muscle is characterized by a combination of a number of properties of the first two types of muscles.
The most remarkable characteristic of skeletal and cardiac muscle fibers when studied using a light microscope is the alternation of light and dark stripes transverse to the long axis of the fiber. Due to this feature, both types of muscles are classified as striated muscles (Fig. 4-1 A, top and middle panels). In smooth muscle, this pattern is absent (Fig. 4-1 A, bottom panel).
IN skeletal muscle thick and thin filaments form a periodic pattern along each myofibril. The regularly repeating element of this pattern is known as sarcomere(from the Greek sarco - muscle, mere - small) (enlarged fragment in Fig. 4-1 B). Each sarcomere contains triad:
1) tank of the sarcoplasmic reticulum;
2) transverse tubule;
3) another tank of the sarcoplasmic reticulum (Fig. 4-1 B).
Figure 4-1 B shows the structure of smooth muscle, which differs from skeletal muscle.
The combined figure 4-1 D shows synchronous recording of action potentials, as well as a mechanogram of skeletal muscle and cardiac muscle.
Rice. 4-1. Organization of fibers and filaments in skeletal and smooth muscles
Muscle types
There are three types of muscles: skeletal, smooth and myocardial. Skeletal muscles are attached to bones, providing support and movement. Smooth muscle surrounds hollow and tubular organs. The cardiac muscle (myocardium) ensures the functioning of the heart.
Skeletal muscles
1.Skeletal muscles consist of cylindrical muscle fibers (cells); each end of the muscle is connected by tendons to bones.
2. Skeletal muscle fibers are characterized by periodic alternation of light and dark stripes, reflecting the spatial organization of thick and thin filaments in myofibrils.
3. Thin filaments containing actin are attached to the Z-bands at both edges of the sarcomere; the free ends of the thin filaments partially overlap with the myosin-containing thick filaments in the A-band of the central part of the sarcomere.
4. During active shortening of skeletal muscle fibers, thin filaments are pulled towards the center of the sarcomere as a result of movements of myosin cross bridges that bind to actin:
The two globular heads of each cross bridge contain an actin-binding site as well as an ATP-splitting enzyme;
Each work cycle of the crossbridge consists of four stages. During contraction, the cross bridges undergo repeated cycles, each of which allows very little advancement of the thin filaments;
ATP performs three functions during muscle contraction.
5. In resting muscle, the attachment of cross bridges to actin is blocked by tropomyosin molecules in contact with thin filament actin subunits.
6. Contraction is initiated as a result of an increase in the cytoplasmic concentration of Ca 2+. When Ca 2+ ions bind to troponin, its conformation changes, due to which tropomyosin shifts, opening access to binding sites on actin molecules; cross bridges bind to thin filaments:
An increase in cytoplasmic Ca 2+ concentration is triggered by an action potential
plasma membrane. The action potential propagates deep into the fiber along the transverse tubules to the sarcoplasmic reticulum and causes the release of Ca 2+ from the reticulum;
Relaxation of the muscle fiber after contraction occurs as a result of active reverse transport of Ca 2+ from the cytoplasm to the sarcoplasmic reticulum.
7.The endings of the motor axon form neuromuscular connections with the muscle fibers of the motor unit of the corresponding motor neuron. Each muscle fiber is innervated by a branch of only one motor neuron:
ACh, released from motor nerve endings upon the arrival of a motor neuron action potential, binds to motor end plate receptors on the muscle membrane; ion channels open, allowing Na+ and K+ to pass through, due to which the end plate is depolarized;
A single motor neuron action potential is sufficient to trigger an action potential in a skeletal muscle fiber.
8. There is a certain sequence of processes leading to contraction of skeletal muscle fiber.
9.The concept of "reduction" refers to the inclusion of the work cycle of the crossbridges. Whether the length of the muscle changes depends on the action of external forces on it.
10.When a muscle fiber is activated, three types of contraction are possible:
Isometric contraction, when the muscle generates tension, but its length does not change;
Isotonic contraction, where the muscle shortens to move the load;
Lengthening contraction, where an external load causes the muscle to lengthen during contractile activity.
11. An increase in the frequency of muscle fiber action potentials is accompanied by an increase in mechanical response (tension or shortening) until the maximum level of tetanic tension is reached.
12. Maximum isometric tetanic tension develops in the case of optimal sarcomere length L o. When the fiber is stretched beyond its optimal length or the fiber length is reduced to less than L o, the stress generated by it drops.
13.The rate of muscle fiber shortening decreases with increasing load. Maximum speed corresponds to zero load.
14.ATP is formed in muscle fibers in the following ways: transfer of phosphate from creatine phosphate to ADP; oxidative phosphorylation of ADP in mitochondria; substrate phosphorylation of ADP during glycolysis.
15.In the beginning physical exercise The main source of energy is muscle glycogen. With longer exercise, energy is generated mainly from glucose and fatty acids, coming with blood; as we continue physical activity the role of fatty acids increases. When the intensity of physical work exceeds ~70% of the maximum, an increasingly significant portion of the resulting ATP begins to be provided by glycolysis.
16. Muscle fatigue is caused by a number of factors, including changes in the acidity of the intracellular environment, decrease in glycogen stores, disruption of electromechanical coupling, but not ATP depletion.
17. There are three types of skeletal muscle fibers depending on the maximum speed of shortening and the predominant method of ATP formation: slow oxidative, fast oxidative and fast glycolytic:
Various maximum speed shortening of fast and slow fibers is due to differences in myosin ATPase: high and low ATPase activity corresponds to fast and slow fibers;
Fast glycolytic fibers have an average larger diameter than oxidative fibers and therefore develop greater tension, but fatigue faster.
18. All muscle fibers of one motor unit belong to the same type; most muscles contain all three types of motor units.
19. The characteristics of three types of skeletal muscle fibers are known.
20.The tension of a whole muscle depends on the amount of tension developed by each fiber and on the number of active fibers in the muscle.
21.Muscles that perform fine movements consist of motor units with a small number of fibers, whereas big muscles, ensuring the maintenance of body posture, consist of much larger motor units.
22.Fast glycolytic motor units contain fibers of larger diameter and, in addition, their motor units have a larger number of fibers.
23.An increase in muscle tension occurs primarily by increasing the number of active motor units, i.e. their involvement. At the beginning of contraction, slow oxidative motor units are the first to be recruited, then fast oxidative motor units and, finally, already with a very intense contraction, fast glycolytic units.
24.Motor unit recruitment is accompanied by an increase in the speed at which the muscle moves the load.
25.Muscle strength and fatigue can be changed through training:
Long-term, low-intensity exercise increases the ability of muscle fibers to produce ATP through the oxidative (aerobic) pathway. This occurs due to an increase in the number of mitochondria and blood vessels in the muscle. As a result, muscle endurance increases;
Short-term, high-intensity exercise increases fiber diameter due to increased actin and myosin synthesis. As a result, muscle strength increases.
26.Joint movements are carried out through two antagonistic muscle groups: flexors and extensors.
27.Muscles together with bones are systems of levers; so that the limb can hold the load, isometric tension muscle should significantly exceed the mass of this load, but the speed of movement of the lever arm is much greater than the speed of shortening of the muscle.
Smooth muscle
1.Smooth muscles can be classified into two large groups: unitary smooth muscles and multiunitary smooth muscles.
2. Smooth muscle fibers - spindle-shaped cells without transverse striations, with one nucleus, capable of division. They contain actin and myosin filaments and contract through a sliding filament mechanism.
3. An increase in the concentration of Ca 2+ in the cytoplasm leads to the binding of Ca 2+ to calmodulin. The Ca 2+ -calmodulin complex then binds to myosin light chain kinase, activating this enzyme, which phosphorylates myosin. Only after phosphorylation
smooth muscle myosin can bind to actin and perform cyclic cross-bridge movements.
4. Smooth muscle myosin hydrolyzes ATP at a relatively low rate, so smooth muscles shorten much more slowly than striated muscles. However, the tension per unit cross-sectional area for smooth muscle is the same as for striated muscle.
5. Ca 2+ ions, which initiate contraction of smooth muscle, come from two sources: the sarcoplasmic reticulum and the extracellular environment. As a result of the opening of calcium channels in the plasma membrane and sarcoplasmic reticulum, which is mediated by various factors, Ca 2+ enters the cytoplasm.
6. Most stimulating factors do not increase the cytoplasmic concentration of Ca 2+ so much that all cross bridges in the cell are activated. That is why factors that increase the concentration of Ca 2+ in the cytoplasm can increase smooth muscle tension.
7. There are certain types of stimuli that cause smooth muscle contraction due to the opening of calcium channels in the plasma membrane and sarcoplasmic reticulum.
8. In the plasma membrane of most smooth muscle cells (but not all), action potentials can be generated when it is depolarized. The ascending phase of the smooth muscle action potential is caused by the entry of Ca 2+ into the cell through the opened calcium channels.
9. In some smooth muscles, action potentials are generated spontaneously, in the absence of external stimuli. This occurs due to the fact that pacemaker potentials periodically arise in the plasma membrane, depolarizing the membrane to a threshold level.
10.Smooth muscle cells lack specialized end plates. Some smooth muscle fibers are affected by neurotransmitters released from varicosities of a single branch of the nerve, and each fiber may be influenced by neurotransmitters from more than one neuron. The effect of neurotransmitters on smooth muscle contractions can be excitatory or inhibitory.
Heart muscle
1. Fast response action potentials are recorded from the atrial and ventricular fibers of the myocardium and from specialized fibers of the ventricular conduction system (Purkinje fibers). The action potential is characterized by a large amplitude, a steep rise, and a relatively long plateau.
2. Slow-response action potentials are recorded in SA and AV node cells and in abnormal cardiomyocytes that have been partially depolarized. The action potential is characterized by a less negative resting potential, smaller amplitude, less steep rise, and shorter plateau than the fast response action potential. The rise is generated by activation of Ca 2+ channels.
3. Action potentials are characterized by an effective refractory period (absolute refractory phase).
4. Automaticity is characteristic of some cells of the SA and AV nodes and of the cells of the ventricular conduction system. A sign of automaticity is the slow depolarization of the membrane during phase 4 (slow diastolic depolarization).
5.Normally, the SA node initiates an impulse that causes the heart to contract. This impulse travels from the SA node through the atrial tissue and ultimately reaches the AV node. After a delay in the AV node, the cardiac impulse spreads through the ventricles.
6. An increase in the length of myocardial fibers, as happens with increased ventricular filling (with preload) during diastole, causes a stronger contraction of the ventricles. The relationship between fiber length and contractile force is known as the Frank-Starling relationship or the Frank-Starling law of the heart.
7. Despite the fact that the myocardium consists of individual cells separated from each other by membranes, the cardiomyocytes that make up the ventricles contract almost in unison, like the cardiomyocytes of the atria. The myocardium functions as a syncytium with an all-or-nothing response when excited. Excitation is carried out from cell to cell through highly permeable contacts - gap junctions, which connect the cytosols of adjacent cells.
Rice. 4-2. General ideas about the structure of various muscles (see table)
8. When excited, voltage-gated calcium channels open and extracellular Ca 2+ enters the cell. The influx of Ca 2+ promotes the release of Ca 2+ from the sarcoplasmic reticulum. The increased concentration of intracellular Ca 2+ causes contraction of myofilaments. Relaxation is accompanied by a restoration of intracellular Ca 2+ concentrations to resting levels by actively pumping Ca 2+ back into the sarcoplasmic reticulum and exchanging Ca 2+ for extracellular Na + across the sarcolemma.
9.The speed and force of contractions depend on the intracellular concentration of free ions
calcium. Force and speed are inversely proportional to each other, so that when there is no load, the speed is maximum. During isovolumic contraction, when there is no external shortening, the total load is maximum and the velocity is zero.
10. When the ventricles contract, the stretching of the muscle fibers with blood during its filling serves as a preload. Afterload is the aortic pressure, overcoming which the left ventricle pushes out blood.
11.Contractility reflects the work of the heart at given values of preload and afterload.
* The number of plus signs (+) indicates the relative size of the sarcoplasmic reticulum in a particular muscle type.
Physiology of skeletal muscles
Concept skeletal, or striated muscle belongs to the group of muscle fibers connected by connective tissue (Fig. 4-3 A). Typically, muscles are attached to bones by bundles of collagen fibers - tendons, located at both ends of the muscle. In some muscles, single fibers are as long as the entire muscle, but in most cases the fibers are shorter and often located at an angle to the longitudinal axis of the muscle. There are very long tendons, they are attached to a bone distant from the end of the muscle. For example, some of the muscles that carry out movements of the fingers are located in the forearm; When we move our fingers, we feel how the muscles of the hand move. These muscles are connected to the fingers through long tendons.
When studied using a light microscope, the main characteristic of skeletal muscle fibers was the alternation of light and dark stripes transverse to the long axis of the fiber. Therefore, skeletal muscles were called cross-striped.
The transverse striation of skeletal muscle fibers is due to the special distribution in their cytoplasm of numerous thick and thin “threads” (filaments), united into cylindrical bundles with a diameter of 1-2 microns - myofibrils(Fig. 4-3 B). The muscle fiber is practically filled with myofibrils; they stretch along its entire length and are connected to tendons at both ends.
Thick and thin filaments form a periodic pattern along each myofibril. Thick filaments consist almost entirely of contractile protein myosin. Thin filaments(their thickness is approximately half the diameter of the thick filament) contain contractile protein actin, as well as two other proteins - troponin
and tropomyosin, which play an important role in the regulation of contraction (see below).
The thick filaments are concentrated in the middle part of each sarcomere, where they lie parallel to each other; this area appears as a wide dark (anisotropic) band called A-band. In both halves of the sarcomere there is a set of thin filaments. One end of each of them is attached to the so-called Z plate(or Z-lines, or Z-band) - a network of intertwining protein molecules - and the other end overlaps with thick filaments. The sarcomere is bounded by two successive Z-bands. Thus, the thin filaments of two adjacent sarcomeres are anchored on the two sides of each Z-band.
Light (isotropic) stripe - the so-called I-band- located between the edges of the A-bands of two adjacent sarcomeres and consists of those areas of thin filaments that do not overlap with thick filaments. The Z-band bisects the I-band.
Within the A-band of each sarcomere, two more stripes are distinguished. A narrow light stripe is visible in the center of the A-band - H-zone. It corresponds to the space between the opposing ends of the two sets of thin filaments of each sarcomere, i.e. includes only the central parts of thick filaments. In the middle of the H-zone there is a very thin dark M-line. This is a network of proteins that connect the central parts of thick filaments. In addition, titin protein filaments go from the Z-band to the M-line, which are associated simultaneously with the M-line proteins and with thick filaments. The M line and titin filaments maintain an orderly organization of thick filaments in the middle of each sarcomere. Thus, thick and thin filaments are not free, unattached intracellular structures.
Rice. 4-3. Structure of skeletal muscles.
A - organization of cylindrical fibers in skeletal muscle attached to bones by tendons. B - structural organization of filaments in a skeletal muscle fiber, creating a pattern of transverse stripes. Shows numerous myofibrils in a single muscle fiber, as well as the organization of thick and thin filaments in the sarcomere
Actin molecule
It is a globular protein consisting of a single polypeptide that polymerizes with other actin molecules and forms two chains that wrap around each other (Figure 4-4 A). This double helix represents the skeleton of a thin filament. Each actin molecule has a myosin binding site. In resting muscle fibers, the interaction between actin and myosin is prevented by two proteins - troponin And tropomyosin(Fig. 4-4 B).
Tropomyosin is a rod-shaped molecule of two polypeptides wrapped around each other; the molecule corresponds in length to approximately seven actin monomers. Chains of tropomyosin molecules, arranged end to end, are located along the entire thin filament. Tropomyosin molecules partially cover the areas, interfering with the contact of myosin with actin. In this blocking position, the tropomyosin molecule is held by troponin.
Troponin is a heterotrimeric protein. It consists of troponin T (responsible for binding to a single molecule of tropomyosin), troponin C (binds Ca 2+ ion) and troponin I (binds actin and inhibits contraction). Each tropomyosin molecule is associated with one heterotrimeric troponin molecule, which regulates access to myosin binding sites on the seven actin monomers adjacent to the tropomyosin molecule.
Myosin
This is a single name for a large family of proteins that have certain differences in the cells of different tissues. Myosin is present in all eukaryotes. About 60 years ago, two types of myosin were known, now called myosin I and myosin II. Myosin II was the first myosin to be discovered and is involved in muscle contraction. Later, myosin I and myosin V were discovered (Fig. 4-4 B). Recently, myosin II has been shown to be involved in muscle contraction, while myosin I and myosin V are involved in the submembrane (cortical) cytoskeleton. Currently, more than 10 classes of myosin have been identified. Figure 4-4D shows two variants of the structure of myosin, which consists of a head, neck and tail. The myosin molecule consists of two large polypeptides (heavy chains) and four smaller ones (light chains). These polypeptides form a molecule with two globular "heads" that contain both types of chains, and a long stem ("tail") of two intertwined heavy chains. The tail of each myosin molecule is located along the axis of the thick filament, and two globular heads protrude from the sides, otherwise called cross bridges. Each globular head has two binding sites: for actin and for ATP. ATP binding sites also have the properties of the enzyme ATPase, which hydrolyzes the bound ATP molecule.
Figure 4-4 E shows the packaging of myosin molecules. The protruding myosin heads are the cross bridges.
Rice. 4-4. The structure of actin and myosin
At rest in the muscle fiber, the concentration of free, ionized Ca 2+ in the cytoplasm around the thick and thin filaments is very low, about 10 -7 mol/l. At this concentration, Ca 2+ ions occupy a very small number of binding sites on troponin molecules (troponin C), so tropomyosin blocks binding to actin cross bridges. After the action potential, the concentration of Ca 2+ ions in the cytoplasm increases rapidly and they bind to troponin, eliminating the blocking effect of tropomyosin and initiating the cross-bridge cycle. The source of Ca 2+ entry into the cytoplasm is sarcoplasmic reticulum muscle fiber.
Sarcoplasmic reticulum muscles is homologous to the endoplasmic reticulum of other cells. It is located around each myofibril like a “ragged sleeve”, the segments of which are surrounded by A- and I-bands. The end parts of each segment expand in the form of so-called lateral sacs(terminal tanks) connected to each other by a series of thinner tubes. Ca 2+ is deposited in the lateral sacs, which is released after stimulation of the plasma membrane (Fig. 4-5 A).
A separate system consists transverse tubules (T-tubules), which cross the muscle fiber at the border lanes A-I, pass between the lateral sacs of two adjacent sarcomeres and emerge on the surface of the fiber, forming a single whole with the plasma membrane. The lumen of the T-tubule is filled with extracellular fluid surrounding the muscle fiber (Fig. 4-5 B). The T-tubule membrane, like the plasma membrane, is capable of conducting an action potential. Originating in
plasma membrane (Fig. 4-5 B), the action potential quickly spreads along the surface of the fiber and along the membrane of the T-tubules deep into the cell. Having reached the region of the T-tubules adjacent to the lateral sacs, the action potential activates the voltage-dependent “gate” proteins of the T-tubule membrane, which are physically or chemically coupled to the calcium channels of the lateral sac membrane. Thus, depolarization of the T-tubule membrane caused by the action potential leads to the opening of calcium channels in the membrane of the lateral sacs containing Ca 2+ in high concentrations, and Ca 2+ ions exit into the cytoplasm. The increase in cytoplasmic Ca 2+ levels is usually sufficient to activate all muscle fiber cross bridges.
The contraction process continues as long as Ca 2+ ions are bound to troponin, i.e. until their concentration in the cytoplasm returns to the low initial value. The membrane of the sarcoplasmic reticulum contains Ca-ATPase, an integral protein that actively transports Ca 2+ from the cytoplasm back into the cavity of the sarcoplasmic reticulum. As just discussed, Ca 2+ is released from the reticulum as a result of action potential propagation along the T-tubules; It takes much longer for Ca 2+ to return to the reticulum than for it to leave. That is why, increased concentration Ca 2+ remains in the cytoplasm for some time, and muscle fiber contraction continues after the end of the action potential.
Summarize. The contraction is due to the release of Ca 2+ ions stored in the sarcoplasmic reticulum. When Ca 2+ flows back into the reticulum, contraction ends and relaxation begins.
Rice. 4-5. Sarcoplasmic reticulum and its role in the mechanism of muscle contraction.
A - diagram of the organization of the sarcoplasmic reticulum, transverse tubules and myofibrils. B - diagram of the anatomical structure of the transverse tubules and sarcoplasmic reticulum in an individual skeletal muscle fiber. B - the role of the sarcoplasmic reticulum in the mechanism of skeletal muscle contraction
This is the sequence of processes by which the action potential of the plasma membrane of a muscle fiber leads to the initiation of muscle contraction, or the so-called cross-bridge cycle, which will be demonstrated later.
The plasma membrane of skeletal muscle is electrically excitable and is capable of generating a propagating action potential through a mechanism similar to that of nerve cells. The action potential in a skeletal muscle fiber lasts 1-2 ms and ends before any signs of mechanical activity appear (Fig. 4-6 A). The onset of mechanical activity can last more than 100 ms. The electrical activity of the plasma membrane does not affect direct influence on contractile proteins, but causes an increase in the cytoplasmic concentration of Ca 2+ ions, which continue to activate the contractile apparatus even after the cessation of the electrical process.
Muscle contraction
In muscle physiology, the term "contraction" should not necessarily be understood as "shortening". First of all, the fact of activation of transverse bridges - areas of force generation in the muscle fiber - is considered. After contraction, the mechanism that initiates the development of force is turned off.
The force with which a muscle, when contracting, acts on an object is called muscular voltage (tension); the force of an object (usually its mass) on a muscle is The forces of muscle tension and load counteract each other. Whether the force generated by a muscle fiber will cause it to shorten depends on the relative magnitudes of tension and
loads. In order for a muscle fiber to shorten and thus move the load, its tension must be greater than the opposing load.
isometric(muscle length is constant). Such a contraction occurs when a muscle holds a load in a constant position or develops a force in relation to a load whose mass is greater than the muscle tension. If a muscle shortens and the load on it remains constant, the contraction is called isotonic
Sliding thread model
As the fiber shortens, each cross bridge attached to the thin filament rotates, much like the rotation of a boat oar. The rotational movements of many cross bridges pull thin filaments from both edges of the A-band to its middle, and the sarcomere shortens (Fig. 4-6 B). One "rake" of the cross bridge creates very little movement of the thin filament relative to the thick filament. However, during the entire period of the active state (excitation) of the muscle fiber, each cross bridge repeats its rotational movement many times, providing a significant displacement of the myofilaments. The detailed molecular mechanism of this phenomenon will be discussed below.
During the generation of force that shortens the muscle fiber, the overlapping thick and thin filaments of each sarcomere, pulled up by the movements of the cross bridges, move relative to each other. The length of thick and thin filaments does not change when the sarcomere is shortened (Fig. 4-6 B). This mechanism of muscle contraction is known as sliding thread model.
Rice. 4-6. The phenomenon of electromechanical coupling.
A - the relationship between the time course of the action potential in the muscle fiber and the resulting contraction of the muscle fiber with its subsequent relaxation. B - cross bridges of thick filaments, binding to the actin of thin filaments, undergo a conformational change, due to which the thin filaments are pulled towards the middle of the sarcomere. (The diagram shows only two of the approximately 200 cross bridges of each thick filament.) B - model of sliding threads. Sliding of overlapping thick and thin filaments relative to each other results in shortening of the myofibril without changes in filament length. The I-disc and H-zone decrease in size
Skeletal muscle specific proteins
As noted, thick and thin filaments form a periodic pattern along each myofibril. A regularly repeating element is a sarcomere. Thick filaments are composed almost entirely of the contractile protein myosin. Thin filaments contain the contractile proteins actin, troponin and tropomyosin. The thick filaments are concentrated in the middle part of each sarcomere, where they lie parallel to each other. This area appears as a wide dark band called the A-band (Fig. 4-7 A). In both halves of the sarcomere there is a set of thin filaments. One end of each of them is attached to the so-called Z-band (or Z-line) - a network of intertwining protein molecules. The other end overlaps with thick filaments. The sarcomere is bounded by two successive Z-bands. Thus, the thin filaments of two adjacent sarcomeres are anchored on the two sides of each Z-band. The light band, the I band, is located between the edges of the A bands of two adjacent sarcomeres and consists of those sections of thin filaments that do not overlap with thick filaments. The Z-band bisects the I-band.
The two ends of each thick filament of the myosin molecule are oriented in opposite directions so that the ends of their tails are directed relative to the center of the filament (Fig. 4-7 B). Due to this, during the rowing movements of the transverse bridges, thin
the filaments of the left and right halves of the sarcomere are pushed towards its middle, as a result of which the sarcomere is shortened. That is, during the generation of force that shortens the muscle fiber, the overlapping thick and thin filaments of each sarcomere move relative to each other, pulled up by the movements of the cross bridges. The length of thick and thin filaments does not change when the sarcomere is shortened
(Fig. 4-7 B).
It is known that within the A-band of each sarcomere two more bands are distinguished. In the center of the A-band, a narrow light stripe is visible - the H-zone. It corresponds to the space between the opposing ends of the two sets of thin filaments of each sarcomere, i.e. includes only the central parts of thick filaments. In the middle of the H-zone there is a very thin dark M-line. This is a network of proteins that connect the central parts of thick filaments. In Fig. 4-7 B show currently known accessory proteins. Protein filaments go from the Z-band to the M-line titina, associated simultaneously with M-line proteins and thick filaments. M-line And titin filaments maintain an orderly organization of thick filaments in the middle of each sarcomere. Thus, thick and thin filaments are not free, unattached intracellular structures. In addition, in Fig. 4-7V shown CapZ protein determining the stabilization of actin filaments. Also shown tropomodulin. The figure also shows a giant protein - nebulin.
Rice. 4-7. The structure of skeletal muscle is normal (A), against the background of relaxation (B) and contraction (C). Additional proteins found in skeletal muscle (D)
Actin and myosin molecule
Thin filament(Fig. 4-8 A) consists of actin, tropomyosin and troponin. The basis of a thin filament is a double twisted chain of an α-helical polymer of the actin molecule. In other words, these are two chains twisted relative to each other. This double helix represents the skeleton of a thin filament. Each helical turn of a single filament, or F-actin, consists of 13 single monomers in the form of globules and is approximately 70 nm in length. Each single actin molecule has a myosin binding site. F-actin is associated with two important regulatory actin-binding proteins - tropomyosin and troponin. These proteins in resting muscle fibers prevent the interaction between actin and myosin. Briefly, tropomyosin molecules partially cover the binding sites of each single actin molecule, interfering with the contact of myosin with actin. In this state of blocking the binding sites of each single actin molecule, the tropomyosin molecule holds troponin. Let's take a closer look at tropomyosin and troponin.
Tropomyosin is a long molecule consisting of two polypeptides wrapped around each other. The tropomyosin molecule is approximately seven actin monomers in length. Chains of tropomyosin molecules, arranged end to end, are located along the entire thin filament. Tropomyosin molecules partially cover areas binding of each actin molecule, blocking the possibility of myosin contact with actin. In this blocking position, the tropomyosin molecule is held by troponin.
Troponin is a heterotrimeric protein. It consists of troponin T, which is responsible for binding to a single tropomyosin molecule, troponin C, which binds Ca 2+ ion, and troponin I, which binds actin and inhibits contraction. Each molecule of tropomyosi-
It is associated with one heterotrimeric troponin molecule, which regulates access to myosin binding sites on seven actin monomers adjacent to the tropomyosin molecule.
Myosin molecule(Fig. 4-8 B) is a single name for a large family of proteins that have certain differences in the cells of different tissues. Participates in muscle contraction myosin II, discovered first among all myosins. In general, the myosin II molecule consists of two large polypeptides (called heavy chains) and four smaller ones (called light chains). In myosin II two heavy chains constitute a molecule containing two globular "heads"(one for each polypeptide) and, accordingly, two untwisted "necks". In some literature, the neck of the heavy chain is translated as “the arm of the myosin molecule.” Next are two large polypeptides, i.e. two heavy chains begin to twist relative to each other. Their initial region of twisting is called "hinge region of heavy chains". This is followed by a long rod of two intertwined heavy chains, called "tail". The tail of each myosin molecule is located along the axis of the thick filament, and the two globular heads, together with the necks and the hinge region, protruding from the sides, are otherwise called "cross bridges". Myosin II has two light chains on each globular head. One is the so-called light regulatory chain, the other is the light main chain. The light main chain is involved in stabilizing the myosin head. The light regulatory chain regulates the activity of the enzyme myosin ATPase, which hydrolyzes the bound ATP molecule. The action of the myosin light regulatory chain is to alter regulation through phosphorylation by Ca 2+ -dependent or Ca 2+ -independent kinases.
The interaction of the thin filament and a single pair of heads from the thick filament myosin is shown in Fig. 4-8 V.
Rice. 4-8. Molecular organization of thin and thick filaments.
A - thin filament. B - myosin molecule. B - interaction of thin and thick filament
Interaction between actin and myosin
Let us consider the question of what allows cross bridges, i.e. globular heads (together with necks and the hinge region), bind to actin and begin to perform a certain movement. In short, muscle contraction is based on a cycle in which myosin II heads bind to actin binding sites. These cross bridges create a curvature that corresponds to the movement of the molecule, after which the myosin heads are separated from the actin. Energy is taken for these cycles ATP hydrolysis. Muscles have mechanisms to regulate cross-bridge cycles. An increase in in initiates the continued formation of cross-bridge cycles. When excited, in increases from the resting level (10 -7 M and less) to more than 10 -5 M.
To begin with, the action potential in a skeletal muscle fiber lasts 1-2 ms and ends before any signs of mechanical activity appear. The onset of mechanical activity can last more than 100 ms. Electrical activity of the plasma membrane does not have a direct influence on contractile proteins, but causes an increase in the cytoplasmic concentration of Ca 2+ ions, which continue to activate the contractile apparatus even after the cessation of the electrical process. That is, the contraction is due to the release of Ca 2+ ions stored in the sarcoplasmic reticulum. When Ca 2+
flows back into the reticulum, contraction ends and relaxation begins. The energy source for the calcium pump is ATP: this is one of the three main functions of ATP in muscle contraction.
So the contraction is initiated as a result of the increase in in . The heterotrimeric troponin molecule contains a key Ca 2+ -sensitive regulator - troponin C. Each troponin C molecule in skeletal muscle has two high-affinity Ca 2+ -binding sites that are involved in the binding of troponin C to the thin filament. Ca 2+ binding at these high-affinity sites is constant and does not change during muscle activity. Each troponin C molecule in skeletal muscle also has two additional low-affinity Ca 2+ -binding sites. The interaction of Ca 2+ with them induces conformational changes in the troponin complex, leading to two effects. The first effect is that the C-terminal of inhibitory troponin I moves away from the actin-myosin binding center (located on actin), thereby moving the tropomyosin molecule also away from the actin-myosin binding center (located on actin). Another effect occurs through troponin T and involves pushing tropomyosin away from the actin-myosin binding site into the so-called actin groove. This causes the myosin binding site on actin to open so that the myosin head can interact with actin, creating a cycle of cross bridges.
Rice. 4-9. Principles of interaction between actin and myosin in skeletal and cardiac muscles
Reduction mechanism
The sequence of events, starting from the binding of the cross bridge to the thin filament until the moment when the system is ready to repeat the process, is called the working cycle of cross bridges. Each cycle consists of four main phases. Phase 1 - the myosin head is tightly bound to the actin molecule into the actomyosin complex. ATP is required to detach the myosin head in the cytosol, and its approach to myosin is shown by the arrow in the diagram. Phase 2 - if the myosin head binds to ATP, then the affinity of the myosin head for actin decreases. Due to the decrease in affinity, the myosin head is separated from the actin molecule. When the effect on the myosin head of ATP is eliminated, the cycle continues further. In muscle, this occurs exclusively due to the breakdown of ATP to ADP+P i as a result of the work of the enzyme myosin ATPase. This step depends on the availability of Mg 2+ . Phase 3 - if on the myosin head after the cleavage of ATP into ADP and Pi, both ADP and Pi are bound. In this case, the myosin head straightens. The affinity of actomyosin complex formation again increases, and the myosin head can reattach the weakly bonded actin molecule. Phase 4 - the initiation of a weak bond transitions quickly into a stronger bond with the ADP-loaded myosin head. The transition to this state represents the actual stage of force generation. This process is explained by the rotation of the myosin head, due to which the rotation of myosin shifts the actin filament one step.
In the cross-bridge cycle, ATP has two different roles:
1)hydrolysis ATP supplies energy for cross-bridge movement;
2)tying(but not hydrolysis) ATP with myosin is accompanied by the separation of myosin from actin and creates the possibility of repeating the cycle of cross bridges.
The chemical and physical phenomena during the four stages of the cross-bridge cycle can be thought of differently. The ATP molecule bound to myosin is cleaved to release chemical energy and form a high-energy cross-bridge myosin conformation; the hydrolysis products of ATP-ADP and inorganic phosphate (Pi) remain associated with this form of myosin (M*).
The energy of the active conformation of myosin can be compared to the potential energy of a stretched spring.
Actin binding.
When the high-energy form of myosin binds to actin, the release of the tense conformation of the high-energy cross-bridge is triggered; As a result, the cross bridge associated with actin undergoes its rotational movement and simultaneously loses ADP and Pi.
Movement of the cross bridge.
The process of sequential acquisition and release of energy by myosin can be compared to the work of a mousetrap. Energy is stored in it when the spring is stretched (in the muscle - during ATP hydrolysis), and released when the spring is released (in the muscle - when myosin binds to actin).
During cross-bridge movement, myosin is very firmly attached to actin; only after breaking this connection can he again receive energy and repeat the cycle. The bond between actin and myosin is broken when a new ATP molecule binds to myosin.
Dissociation of the cross bridge from actin.
The ATP-mediated separation of actin and myosin is an example of allosteric regulation of protein activity. The binding of ATP to one site of myosin reduces the affinity of its molecule for actin bound to another site. Therefore, ATP acts as a modulator to regulate the binding of actin to myosin. Note that at this stage ATP is not broken down, i.e. does not serve as a source of energy, but only as a modulating molecule, which provides allosteric modulation of the myosin head and thereby weakens the connection of myosin with actin.
Rice. 4-10. Reduction mechanism. The working cycle of the cross bridges - the myosin head (together with the neck and hinge region) is presented.
In panel (A) the process is represented as a closed cycle of four phases. Panel (B) presents the process in more detail in the form of successive steps.
Single muscle contraction
If a muscle develops tension but does not shorten (or lengthen), the contraction is called isometric(muscle length is constant). Such a contraction occurs when a muscle holds a load in a constant position, or develops a force in relation to a load whose mass is greater than the muscle tension. If a muscle shortens and the load on it remains constant, the contraction is called isotonic(muscle tension is constant).
The mechanical response of an individual muscle fiber to a single action potential is called single contraction(twitch). Basic characteristics of a single isometric contraction shown in Fig. 4-11 A. The onset of muscle tension is delayed by several milliseconds relative to the action potential. During this latent period pass all stages of electromechanical coupling. The interval from the beginning of voltage development to the moment of its maximum is reduction time. It is different for different types of skeletal muscle fibers. The contraction time of fast fibers does not exceed 10 ms, while for slower fibers it is not less than 100 ms. The duration of contraction is determined by how long the cytoplasmic Ca 2+ concentration remains elevated, allowing continued cyclic cross-bridge activity. The contraction time is determined by the activity of Ca-ATPase of the sarcoplasmic reticulum, which is higher in fast fibers than in slow fibers.
The characteristics of isotonic contraction also depend on the mass of the load being lifted (Fig. 4-11 B), namely, with a heavier load:
1) the latent period is longer;
2) the speed of shortening (the amount of muscle shortening per unit time), the duration of contraction and the amount of muscle shortening are less.
A comparison of single contractions of the same muscle fiber under different modes of its activity shows (Fig. 4-11 B) that the latent period is longer for an isotonic contraction than for an isometric one, while the duration of the mechanical process is shorter in the case of an isotonic contraction (i.e. . during shortening) than isometric (i.e. when generating force).
Let us consider in more detail the sequence of phenomena during an isotonic single contraction. When a muscle fiber is excited, the cross bridges begin to develop force, but shortening will not begin until the muscle tension exceeds the load on the fiber. Thus, the shortening is preceded by a period isometric contraction, during which the tension increases. The heavier the load, the longer it will take for the voltage to equal the load and shortening to begin. If the load is increased, then, in the end, the muscle fiber will not be able to lift it, the speed and degree of shortening will be zero and the contraction will become completely isometric.
Note that the force with which a muscle acts on an object during its contraction is called muscular voltage (tension). The force of an object (usually its mass) on a muscle is Since ancient times, the curve of muscle contraction in Russian literature has been called a “mechanogram”, i.e. recording the mechanical activity of the muscle. In world literature the concepts are usually used resting tension (force) to describe the force with which a resting muscle acts on an object (in mN), and active tension (force) to describe the force with which a muscle, when it contracts, acts on an object.
The forces of muscle tension and load counteract each other. Whether the force generated by a muscle fiber will cause it to shorten depends on the relative magnitudes of tension and load. In order for a muscle fiber to shorten and thus move a load, its tension must be greater than the opposing load.
Rice. 4-11. Single muscle contraction.
A - single isometric contraction of a skeletal muscle fiber after one action potential. B - single isotonic contractions under different loads. The magnitude, speed, and duration of shortening decrease with increasing load, whereas the time interval from stimulus to onset of shortening increases with increasing load. B - single isotonic contraction of a skeletal muscle fiber after one action potential
Kinds muscle contractions
Since the duration of one action potential in a skeletal muscle fiber is 1-2 ms, and a single contraction can last 100 ms, the moment of initiation of the second action potential may fall during the period of mechanical activity. Figure 4-12 A-B shows isometric contractions of a muscle fiber in response to three successive stimuli. The isometric contraction in response to the first stimulus S 1 lasted 150 ms (Fig. 4-12 A). The second stimulus S2, given 200 ms after S1, when the muscle fiber had already completely relaxed, caused a second contraction identical to the first, and the third stimulus S3 with the same interval caused a third identical contraction. In Figure 4-12 B, the S 1 -S 2 interval remained at 200 ms, and the third stimulus was presented 60 ms after S 2, when the mechanical response to S 2 began to decline but had not yet ended. The S 3 stimulus evoked a contractile response, the maximum voltage of which exceeded the response to S 2 . In Figure 4-12 B, the S 2 -S 3 interval was reduced to 10 ms, and the maximum mechanical response increased even further, with the response to S 3 appearing to be a fused continuation of the response to S 2 .
The increase in muscle tension during successive action potentials occurring before the end of the mechanical activity phase is called summation. When single contractions merge during rhythmic stimulation, tetanus(tetanic contraction). At low stimulation frequencies, the mechanical response may be wave-like as the fiber partially relaxes between stimuli; This serrated tetanus. If the frequency of stimulation is increased, a smooth tetanus is obtained, without oscillations (Fig. 4-12 D).
As the frequency of action potentials increases, the magnitude of the voltage increases as a result of summation until the smooth tetanus reaches a maximum, after which the voltage will not increase with a further increase in the frequency of stimulation.
To explain the reasons for the summation, it is necessary to consider what processes occur in the muscle fibers. But first you should obtain information about the elastic properties of the muscle. The muscle contains passive elastic elements (areas of thick and thin filaments, as well as tendons) connected in series with contractile elements (those generating force). Consecutive
the elastic elements act as springs through which the active force generated by the cross bridges is transmitted to the load. Time course of voltage at isometric contraction includes the period required for stretching successive elastic elements.
The tension of a muscle fiber at a particular point in time depends on the following factors:
1) the number of cross bridges attached to actin and located at the 2nd stage of the cross bridge cycle in each sarcomere;
2) the force created by each cross bridge;
3) the duration of the active state of the cross bridges.
One action potential causes the muscle fiber to release enough Ca 2+ to saturate troponin, so all myosin binding sites on the thin filaments are initially accessible. However, binding of the high-energy cross-bridge form to these areas (stage 1 of the cross-bridge cycle) takes some time, and in addition, as noted above, time is required for the successive elastic elements to stretch. As a result, despite the initial availability of all binding sites during a single contraction, maximum tension does not develop immediately. Another circumstance: almost immediately after the release of Ca 2+ ions, their reverse transfer into the sarcoplasmic reticulum begins, so that the concentration of Ca 2+ in the cytoplasm gradually decreases relative to the previous high level and, consequently, fewer and fewer myosin binding sites remain on the actin filaments that can interact with cross bridges.
The situation is different during tetanic contraction. Each successive action potential causes the release of Ca 2+ from the sarcoplasmic reticulum before the reverse transfer of all Ca 2+ ions present in the cytoplasm after the previous action potential ends. Thanks to this, the increased cytoplasmic concentration of Ca 2+ is steadily maintained and, therefore, the number of sites on actin filaments available for binding to myosin does not decrease. As a result, the number of sites available for binding remains at the maximum level, the cyclic activity of the cross bridges ensures sufficient stretching of successive elastic elements and transmission of maximum tension to the ends of the muscle fiber.
Rice. 4-12. Relationship between frequency and voltage.
A-B - summation of contractions as a result of decreasing time intervals between stimuli S 2 and S 3. G - isometric contractions caused by a series of stimuli with a frequency of 10/s (dentate tetanus) and 100/s (fused tetanus); a single contraction is shown for comparison
Relationship between load and shortening speed
The rate of muscle fiber shortening decreases with increasing load (Fig. 4-13 A). The rate of shortening is maximum when there is no load and is zero when the load corresponds to the force of maximum isometric tension. If the load becomes greater than the maximum isometric strain, elongation muscle fiber at a rate that increases with increasing load; under very heavy load the fiber will break.
The rate of shortening is determined by the frequency at which each cross-bridge cycles and, ultimately, by the rate of ATP cleavage, since one ATP molecule is cleaved in each cross-bridge cycle. If the load on the cross bridge increases, ATP molecules undergo hydrolysis less frequently (for a number of reasons) and, consequently, the rate of shortening decreases.
The relationship between muscle length and tension
Passive The elastic properties of a relaxed muscle are determined mainly by the peculiarities of the organization of the titin protein, the molecule of which is attached at one end to the Z-band, at the other to a thick filament, and acts like a spring. As the muscle stretches, the passive tension of the relaxed fiber increases, but not due to the active movements of the transverse bridges, but due to the stretching of the titin filaments. If the stretched fiber is released, its length will return to its equilibrium state, just as a strip of rubber contracts in a similar situation. Stretching leads not only to passive tension of the muscle fiber, but also to a change in its active tension during contraction. Therefore, the force generated during contraction depends on the initial length of the muscle fiber. This is illustrated by an experiment where a muscle fiber is stretched, and at each length the amount of active tension in response to stimuli is recorded (Fig. 4-13 B). The length at which the fiber generates the greatest active isometric stress is called optimal length,
With a muscle fiber length equal to 60% of L o , the fiber does not generate tension in response
to the stimulus. As the fiber is stretched from this initial level, the active isometric stress increases at each length until it reaches a maximum at length L o . As the fiber continues to elongate, its tension falls. With a length of 175% or more of L o , the fiber does not respond to irritation.
When skeletal muscles are relaxed, the length of most of their fibers approaches L o and is therefore optimal for generating force. Relaxed fiber length changes under load or as a result of stretch caused by contraction of other muscles, but passive change in relaxed fiber length is limited because muscles are attached to bone. The passive change in length rarely exceeds 30% and is often much less. In this range of initial length values, the active muscle tension never falls below half the tension developed at L o (Fig. 4-13 B).
The relationship between the initial fiber length and its ability to develop active tension during contraction can be explained in terms of the sliding filament model. When a relaxed muscle fiber is stretched, thin filaments are pulled out from bundles of thick filaments, so that the area of overlap is reduced. If the fiber is stretched to 1.75 L o , the filaments no longer overlap. The cross bridges cannot bind to actin and tension does not develop. With less stretching (a gradual change in length from 1.75 L o to L o), the zone of filament overlap increases, and the tension developed during stimulation increases in direct proportion to the increase in the number of cross bridges in the overlap zone. The largest overlap zone occurs at length L o ; then the largest number of cross bridges can attach to the thin filaments and the voltage generated is maximum.
If the fiber length is less than L o , the developed voltage is reduced due to a number of circumstances. First, bundles of thin filaments from opposite ends of the sarcomere begin to overlap, interfering with cross-bridge attachment and force development. Secondly, for reasons that are still unclear, as the fiber length decreases, the affinity of troponin for Ca 2+ decreases and, consequently, the number of sites available for binding to cross bridges on thin filaments decreases.
Rice. 4-13. Two main relationships: load - muscle shortening rate, length - muscle tension.
A is the rate of shortening and lengthening of skeletal muscle fibers depending on the load. Note that the force acting on the cross bridges during the lengthening contraction is greater than the maximum isometric tension. B - changes in active isometric tetanic tension depending on the length of the muscle fiber. The blue area corresponds to the physiological range of fiber lengths in muscle attached to bone
Functional role of ATP in the process of skeletal muscle contraction
1. As a result of ATP hydrolysis caused by myosin, the cross bridges receive energy for the development of pulling force.
2. The binding of ATP to myosin is accompanied by the detachment of cross bridges attached to actin.
3. ATP hydrolysis under the action of Ca-ATPase of the sarcoplasmic reticulum supplies energy for the active transport of Ca 2+ into the lateral sacs of the sarcoplasmic reticulum, which leads to a decrease in cytoplasmic Ca 2+ to the initial level. Accordingly, the contraction ends and the muscle fiber relaxes.
In skeletal muscles, during their transition from a state of rest to contractile activity, the rate of ATP breakdown increases sharply by 20 times (or even several hundred times). The small supply of ATP in skeletal muscle is sufficient for only a few single contractions. To maintain long-term contraction, ATP molecules must be generated by metabolism at the same rate as they are broken down during contraction.
There are three ways that ATP is produced during muscle fiber contraction (Figure 4-14):
1) phosphorylation of ADP by transfer of a phosphate group from creatine phosphate;
2) oxidative phosphorylation of ADP in mitochondria;
3) phosphorylation of ADP during glycolysis in the cytoplasm.
Thanks to phosphorylation of ADP by creatine phosphate, very rapid formation of ATP is ensured at the very beginning of contraction:
During the resting period, the concentration of creatine phosphate in the muscle fiber increases to a level approximately five times higher than the ATP content. At the beginning of contraction, when the concentration of ATP decreases and the concentration of ADP increases due to the breakdown of ATP by the action of myosin ATPase, the reaction shifts towards the formation of ATP due to creatine phosphate. In this case, the energy transition occurs at such a high speed that at the beginning of contraction
the ATP concentration in the muscle fiber changes little, while the creatine phosphate concentration drops quickly.
Although ATP is produced very quickly by creatine phosphate through a single enzymatic reaction, the amount of ATP is limited by the initial concentration of creatine phosphate in the cell. In order for muscle contraction to last longer than a few seconds, the participation of the other two sources of ATP formation mentioned above is necessary. Once the contraction achieved by creatine phosphate begins, the slower, multi-enzyme pathways of oxidative phosphorylation and glycolysis are activated to increase the rate of ATP production to match the rate of ATP breakdown.
With moderate muscle activity, ATP is formed predominantly by oxidative phosphorylation, and during the first 5-10 minutes the main resource for this is glycogen. In the next ~30 min, energy sources delivered by the blood become dominant, with glucose and fatty acids participating to approximately the same extent. At later stages of contraction, utilization of fatty acids predominates, and less glucose is consumed.
If the intensity of muscle work is such that the rate of ATP breakdown exceeds 70% of its maximum level, the contribution of glycolysis to the formation of ATP increases significantly. Glucose for this process comes from two sources: from the blood or from glycogen stores in muscle fibers. As muscle activity increases, the proportion of ATP provided by the anaerobic process - glycolysis - increases; Accordingly, more lactic acid is formed.
At the end of muscular work, the reserves of energy-rich compounds (creatine phosphate and glycogen) in the muscle are reduced. To restore the reserves of both compounds, energy is needed, so the muscle, already at rest, continues to intensively consume oxygen for some time. Thanks to the increased oxygen consumption in the period after muscular work, the so-called oxygen debt; and intensive ATP formation through oxidative phosphorylation is aimed at restoring energy resources in the form of creatine phosphate and glycogen.
Rice. 4-14. Energy metabolism of skeletal muscle.
Three resources for the formation of ATP during muscle contraction: 1 - creatine phosphate; 2 - oxidative phosphorylation; 3 - glycolysis
Skeletal muscle fiber types
Skeletal muscle fibers vary in their mechanical and metabolic characteristics. Fiber types are differentiated based on the following characteristics:
1) depending on the maximum speed of shortening - fast and slow fibers;
2) depending on the main path of ATP formation - oxidative and glycolytic fibers.
Fast and slow muscle fibers contain myosin isoenzymes that break down ATP at different maximum rates, which correspond to different maximum cross-bridge operating cycle rates and, therefore, different maximum fiber shortening rates. High ATPase activity of myosin is characteristic fast fibers lower ATPase activity - slow fibers. Although fast fibers have a duty cycle rate approximately 4 times higher than slow fibers, both types of cross bridges generate the same force.
Another approach to classifying skeletal muscle fibers is based on differences in the enzymatic mechanisms of ATP synthesis. Some fibers contain many mitochondria and therefore have high levels of oxidative phosphorylation; This oxidative fibers. The amount of ATP formed in them depends on the supply of blood to the muscle, which carries oxygen molecules, and energy-rich compounds. Fibers of this type are surrounded by numerous capillaries. In addition, they contain oxygen-binding protein - myoglobin, which increases the rate of oxygen diffusion and also serves as a short-term oxygen depot in muscle tissue. Due to the significant content of myoglobin, oxidative fibers are dark red; they are often called red muscle fibers.
IN glycolytic fibers on the contrary, there are few mitochondria, but a high content of glycolytic enzymes and large glycogen reserves. These fibers are surrounded by a relatively small number of capillaries, and there is little myoglobin in their tissue, which corresponds to limited oxygen use. Due to lack
myoglobin glycolytic fibers look light and are called white muscle fibers.
Based on the two characteristics considered (shortening rate and type of metabolism), three types of skeletal muscle fibers can be distinguished.
1.Slow oxidative fibers(type I) - low myosin ATPase activity and high oxidative capacity (Fig. 4-15 A).
2.Fast oxidative fibers(type IIa) - high activity of myosin ATPase and high oxidative capacity (Fig. 4-15 B).
3.Fast Glycolytic Fibers(type IIb) - high myosin ATPase activity and high glycolytic ability
(Fig. 4-15 B).
Note that the fourth theoretically has not been discovered possible variant- slow glycolytic fibers.
Fibers vary not only in their biochemical features, but also in size: glycolytic fibers have a significantly larger diameter than oxidative ones. This affects the amount of voltage they develop. As for the number of thick and thin filaments per unit cross-sectional area, it is approximately the same for all types of skeletal muscle fibers. Thus, the larger the fiber diameter, the greater the number of parallel thick and thin filaments involved in generating force, and the greater the maximum tension of the muscle fiber. It follows that the glycolytic fiber, which has a larger diameter, develops, on average, a greater tension compared to the tension of the oxidative fiber.
In addition, the three types of muscle fibers considered are characterized by different resistance to fatigue. Fast glycolytic fibers fatigue after a short time, while slow oxidative fibers are very hardy, which allows them to maintain contractile activity for a long time at an almost constant level of tension. Fast oxidative fibers are intermediate in their ability to resist the development of fatigue.
The characteristics of the three types of skeletal muscle fibers are summarized in Table. 4-1.
Rice. 4-15. Types of skeletal muscle fibers. The rate of development of fatigue in three types of fibers.
Each vertical line corresponds to a contractile response to a brief tetanic stimulation. Contractive responses between 9 and 60 min are omitted
Table 4-1.Characteristics of the Three Types of Skeletal Muscle Fibers
Muscle tension
The force with which a muscle acts on an object when it contracts is called muscle force. voltage (tension); the force of an object (usually its mass) on a muscle is If a muscle is given a background load, as is usually done during measurements, then this background load is called preload - preload or prestretch. This is often written in Russian spelling - "prelode" The forces of muscle tension and load counteract each other. Whether the force generated by a muscle fiber will cause it to shorten depends on the relative magnitudes of tension and load. In order for a muscle fiber to shorten and thus move the load, its tension must be greater than the opposing load.
If a muscle develops tension but does not shorten (or lengthen), the contraction is called isometric(the length of the muscle is constant) (Fig. 4-16 A). Such a contraction occurs when a muscle holds a load in a constant position or develops a force in relation to a load whose mass is greater than the muscle tension. If a muscle shortens and the load on it remains constant, the contraction is called isotonic(muscle tension is constant) (Fig. 4-16 B).
The third type of contraction is lengthening contraction (eccentric contraction), when the load acting on the muscle is greater than the tension developed by the cross bridges. In this situation, the load stretches the muscle, despite the opposing force created by the movements of the cross bridges. An eccentric contraction occurs when an object supported by a muscle moves downward (examples: a person sits down from a standing position or walks down a
stairs). It should be emphasized that under such conditions, the elongation of muscle fibers is not an active process carried out by contractile proteins, but the result of an external force acting on the muscle. In the absence of an external force lengthening the muscle, the fiber, when stimulated, will only shorten, but don't lengthen. All three types of contractions (isometric, isotonic and eccentric) are natural events of daily activity.
With each type of contraction, the cross bridges rhythmically repeat a cycle consisting of four stages. At the 2nd stage of isotonic contraction, the cross-bridges associated with actin undergo a rotational movement, causing the sarcomeres to shorten. It happens differently during isometric contraction: due to the load acting on the muscle, the cross bridges associated with actin cannot move the thin filaments, but transmit force to them - isometric tension. During stage 2 of eccentric contraction, the crossbridges experience a load that pulls them back toward the Z-plate, while they remain attached to the actin and develop force. Stages 1, 3 and 4 are the same for all three types of contractions. Thus, with each type of contraction, the contractile proteins undergo the same chemical changes. The final result (shortening, no change in length, or lengthening) is determined by the amount of load on the muscle.
Figure 4-16B shows the relationship "length-tension" with isometric contraction, and in Fig. 4-16 G is only the “active” fragment of this dependence, i.e. difference between the "passive" curve and the general curve. The following shows (Fig. 4-16 E) characteristic curves reflecting the “load-speed” relationship.
Rice. 4-16. Isometric and isotonic contraction.
A - experimental drug for studying muscle contractions under isometric conditions. B - experimental drug for studying muscle contractions under isotonic conditions. B - passive curve demonstrating muscle tension (tension), which is measured at various muscle lengths before contraction. Summary curve showing muscle tension (tension), which is measured at different muscle lengths during contraction. G - active muscle tension (active tension) represents the difference between total and passive muscle tension on panel (C). D - three blue curves show that the rate of muscle shortening is faster if the muscle is stretched by mass
Musculoskeletal system
The contracting muscle transmits force to the bones through the tendons. If the force is sufficient, then when the muscles shorten, the bones move. When a muscle contracts, it develops only a pulling force, so that the bones to which it is attached are pulled towards each other as it shortens. In this case it may happen bending limbs in a joint (flexion) or extension(extension) - straightening of the limb (Fig. 4-17 A). These opposing movements must involve at least two different muscles - the flexor and the extensor. Muscle groups that carry out joint movements in opposite directions are called antagonists. As shown in Fig. 4-17 A, with contraction of the biceps brachii muscle (m. biceps) the hand bends in elbow joint, while contraction of the antagonist muscle - the triceps brachii muscle (m. triceps) causes the arm to extend. When contracting, both muscles create only a pulling force in relation to the forearm.
Antagonist muscle groups are necessary not only for flexion and extension, but also for lateral movement of the limbs or for rotation. Some muscles, when contracted, can create two types of movement depending on the contractile activity of other muscles acting on the same limb. For example, when reducing calf muscle(m. gastrocnemius) the leg bends at the knee, for example, while walking (Fig. 4-17 B). However, if the gastrocnemius muscle contracts simultaneously with the quadriceps femoris muscle (m. quadriceps femoris), which straightens the leg at the shin, the knee joint cannot bend, so movement is only possible at the ankle joint. The foot is extended, i.e. a person rises on the tips of his toes - “stands on tiptoes.”
The muscles, bones and joints of the body are systems of levers. The principle of operation of the lever can be illustrated using the example of forearm flexion (Fig. 4-17 B): biceps exerts a pulling force directed upward on a section of the forearm approximately 5 cm from the elbow joint. In the example under consideration, the hand holds a load of 10 kg, i.e. At a distance of approximately 35 cm from the elbow, a downward force of 10 kg acts. According to the laws of physics, the forearm is in a state of mechanical equilibrium (i.e., the total force acting on the system is zero) when the product of the downward force (10 kg) and the distance from the place of its application to the elbow (35 cm) is equal to the product of the isometric muscle tension (X) at a distance from it to the elbow (5 cm). So, 10x35=5xX; hence X=70 kg. Note that the operation of this system is mechanically disadvantageous, since the force developed by the muscle is much greater than the mass of the load being held (10 kg).
However, the mechanically unfavorable operating conditions of most muscle lever mechanisms are compensated for by increased maneuverability. Figure 4-17 shows that shortening the biceps muscle by 1 cm corresponds to moving the hand a distance of 7 cm. Since the shortening of the muscle by 1 cm and moving the hand by 7 cm occur in the same time, the speed of movement of the hand is seven times greater, than the rate of muscle shortening. The lever system acts as an amplifier, thanks to which small, relatively slow movements of the biceps muscle are converted into faster movements of the hand. Thus, a ball thrown by a basketball team's serve travels at a speed of 90-100 mph (approximately 150-160 km/h), although the player's muscles shorten many times slower.
Rice. 4-17. Muscles and bones act as a lever system.
A - antagonist muscles that perform flexion and extension of the forearm. B - contraction of the gastrocnemius muscle leads to flexion of the lower limb when the quadriceps muscle is relaxed, or to extension when the latter contracts, preventing the knee joint from bending. B - mechanical equilibrium of forces acting on the forearm when the hand holds a load of 10 kg. The G-lever system of the arm acts as an amplifier in relation to the speed of contraction of the biceps brachii muscle, increasing the speed of movement of the hand. The system is also an amplifier of the range of movement of the hand (when the muscle is shortened by 1 cm, the hand moves by 7 cm)
Neuromuscular junction
The signal to trigger contraction is the action potential of the plasma membrane of the skeletal muscle fiber. In skeletal muscles, action potentials can be evoked only in one way - stimulation of nerve fibers.
Skeletal muscle fibers are innervated by the axons of nerve cells called motor neurons(or somatic efferent neurons). The bodies of these cells are located in the brain stem or in spinal cord. Motor neuron axons are covered with a myelin sheath and are larger in diameter than other axons, so they conduct action potentials at high speeds, ensuring that signals from the central nervous system reach skeletal muscle fibers with only minimal delay.
Having entered the muscle, the motor neuron axon divides into many branches, each of which forms one connection with the muscle fiber. One motor neuron innervates many muscle fibers, but each muscle fiber is controlled by a branch from only one motor neuron. A motor neuron, together with the muscle fibers it innervates, makes up motor unit. The muscle fibers of one motor unit are located in the same muscle, but not in the form of a compact group, but are scattered throughout the muscle. When an action potential occurs in a motor neuron, all muscle fibers of its motor unit are stimulated to contract.
As the axon approaches the surface of the muscle fiber, the myelin sheath ends, and the axon forms a terminal part (nerve ending) in the form of several short processes located in grooves on the surface of the muscle fiber. The area of the plasma membrane of the muscle fiber, lying directly under the nerve ending, has special properties and is called motor end plate. The structure consisting of a nerve ending and a motor end plate is known as neuromuscular junction(neuromuscular junction).
Motor neuron axon terminals (motor nerve endings) contain vesicles filled with ACh. The action potential coming from the motor neuron depolarizes the plasma membrane of the nerve ending, as a result of which voltage-gated Ca 2+ channels open, and Ca 2+ from the extracellular environment enters the nerve ending. Ca 2+ ions bind to proteins,
ensuring the fusion of the vesicle membrane with the plasma membrane of the nerve ending, and ACh is released into the synaptic cleft separating the nerve ending and the motor end plate. ACh molecules diffuse from the nerve ending to the motor end plate, where they bind to nicotinic acetylcholine receptors, opening ion channels that are permeable to both Na+ and K+. Due to the difference in the transmembrane electrochemical gradients of these ions, the Na + flow entering the muscle fiber is greater than the K + flow out, resulting in local depolarization of the motor end plate - end plate potential(PKP). EPP is similar to EPSP at interneuron synapses. However, the amplitude of a single EPP is substantially higher than the amplitude of the EPSP because at the neuromuscular junction the released neurotransmitter reaches a larger surface area where it binds to many more receptors and where, therefore, many more ion channels open. For this reason, the amplitude of a single EPP is usually more than sufficient to generate a local electrical current in the muscle plasma membrane adjacent to the end plate, initiating an action potential. The action potential then propagates across the surface of the muscle fiber through the same mechanism as in the axon membrane. Most neuromuscular junctions are located in the middle part of the muscle fiber, from where the resulting action potential propagates to both ends of the fiber. In human skeletal muscle, inhibitory potentials never arise. All neuromuscular connections are excitatory.
Along with the ACh receptors, an enzyme is present on the motor end plate acetycholinesterase(ACH esterase), which cleaves ACH. As the concentration of free ACh decreases due to its cleavage by ACh esterase, the amount of ACh capable of binding to receptors decreases. When there are no ACh-bound receptors left, the endplate ion channels become closed. Depolarization of the end plate is completed, the membrane potential returns to the resting level, and the end plate is again able to respond to the ACh released when the next action potential arrives at the nerve terminal.
Rice. 4-18. Excitation of the muscle fiber membrane: neuromuscular junction
Electromechanical interface
Early studies of the isolated heart revealed that optimal concentrations of Na + , K + and Ca 2+ are required for cardiac muscle contraction. Without Na +, the heart is inexcitable and will not beat, since the action potential depends on extracellular sodium ions. In contrast, the resting membrane potential is independent of the transmembrane Na + ion gradient. Under normal conditions, the extracellular concentration of K+ is about 4 mM. Reducing the concentration of extracellular K + does not have a major effect on the excitation and contraction of the heart muscle. However, increasing the concentration of extracellular K + to sufficiently high levels causes depolarization, loss of excitability of myocardial cells and cardiac arrest in diastole. Ca 2+ is also essential for heart contraction. Removal of Ca 2+ from the extracellular fluid leads to a decrease in the strength of heart contractions and subsequent cardiac arrest in diastole. On the contrary, an increase in the concentration of extracellular Ca 2+ increases cardiac contractions, and very high concentrations of Ca 2+ lead to cardiac arrest in systole. Free intracellular Ca 2+ serves as the ion responsible for myocardial contractility.
The two panels of the figure show the electromechanical coupling mechanisms in the heart described below. Excitation of the heart muscle begins when a wave of excitation quickly spreads along the sarcolemma of myocardial cells from cell to cell through gap junctions. Excitation also spreads into the cells through transverse tubes that are invaginated into the cardiac fibers at the Z-bands. Electrical stimulation in the Z-band region or application of ionized Ca 2+ in the Z-band region of cardiac fibers freed from the membrane (with sarcolemmas removed) causes local contraction of neighboring myofibrils. During the plateau of the action potential, the permeability of the sarcolemma to Ca 2+ increases. Ca 2+ enters the cell along its electrochemical gradient through calcium channels of the sarcolemma and its invaginations, i.e. through the membranes of the T-system.
The opening of calcium channels is thought to result from phosphorylation of channel proteins by cyclic adenosine monophosphate-dependent protein kinase (cAMP-dependent protein kinase). The initial source of extracellular Ca 2+ is interstitial fluid (10 -3 M Ca 2+). Some
the amount of Ca 2+ may also be associated with the sarcolemma and with glycocalyx, mucopolysaccharide covering the sarcolemma. The amount of calcium entering the cell from the extracellular space is not enough to cause contraction of myofibrils. Calcium that enters (“triggering or triggering” Ca 2+) triggers the release of Ca 2+ from the sarcoplasmic reticulum (where there is a supply of intracellular Ca 2+). The concentration of free Ca 2+ in the cytoplasm increases from the resting level (resting level) at approximately 10 -7 M to levels of 10 -6 to 10 -5 M during excitation. Ca 2+ then binds to the protein troponin C. The calcium-troponin complex interacts with tropomyosin to remove the block from the active sites between the actin and myosin filaments. This release of the block allows the formation of cyclic cross-links between actin and myosin and therefore allows the myofibrils to contract.
Mechanisms that increase the concentration of Ca 2+ in the cytosol increase the developed force of cardiac contractions (active force), and mechanisms that reduce the cytosolic Ca 2+ concentration reduce it. For example, catecholamines increase the entry of Ca 2+ into the cell by phosphorylating channels through cAMP-dependent protein kinase. In addition, catecholamines, like other agonists, increase the force of heart contractions by increasing the sensitivity of the contractile mechanism to Ca 2+. An increase in the concentration of extracellular Ca 2+ or a decrease in the Na + gradient across the sarcolemma also leads to an increase in the concentration of Ca 2+ in the cytosol.
The sodium gradient can be lowered by increasing the intracellular Na + concentration or by decreasing the extracellular Na + concentration. Cardiac glycosides increase the intracellular concentration of Na + by “poisoning” Na + /K + -ATPase, which leads to the accumulation of Na + in cells. An increase in Na + concentration in the cytosol changes the direction of the Na + /Ca 2+ exchanger (Na + /Ca 2+ -exchanger) the opposite, so that less Ca 2+ is removed from the cell. The reduced concentration of extracellular Na + causes less Na + to enter the cell, and thus less Na + is replaced by Ca 2+ .
Achieved mechanical stress (tension) decreases due to a decrease in the concentration of extracellular Ca 2+, an increase in the transmembrane Na + gradient, or the use of Ca 2+ channel blockers, which prevent the entry of Ca 2+ into myocardial cells.
Rice. 4-19. Electromechanical coupling in the heart
Smooth muscle physiology
Smooth muscle fiber is a spindle-shaped cell with a diameter of 2 to 10 microns. Unlike multinucleated skeletal muscle fibers, which can no longer divide after differentiation is completed, smooth muscle fibers have a single nucleus and are capable of dividing throughout the life of the organism. Division begins in response to a variety of paracrine signals, often to tissue damage.
The significant variety of factors that modify the contractile activity of smooth muscles of various organs makes it difficult to classify smooth muscle fibers. However there is general principle, based on the electrical characteristics of the plasma membrane. According to this principle, most smooth muscles can be classified into one of two types: unitary smooth muscles(single-unit smooth muscles) with fibers connected into a single whole (Fig. 4-20 A), the cells of which interact through gap junction And multiunitary smooth muscle(multiunit smooth muscles) with individual innervation of fibers (Fig. 4-20 B).
Unitary smooth muscles
In muscles of this type, activity (electrical and mechanical) is carried out by different cells synchronously, i.e. The muscle reacts to stimuli as a whole. This is due to the fact that muscle fibers are connected to each other gap junction(gap junctions), through which an action potential can propagate from one cell to neighboring cells through local currents. Thus, electrical activity generated in any unitary smooth muscle cell is transmitted to all fibers (Fig. 4-20 A).
Some fibers of unitary smooth muscles have pacemaker properties. Action potentials spontaneously arise in them and are conducted through gap junction to fibers that do not have such activity. Most unitary smooth muscle cells are not pacemaker.
The contractile activity of unitary smooth muscles is influenced by the electrical activity of nerves, hormones, and local factors;
these influences are mediated by the mechanisms discussed above in relation to the activity of all smooth muscles. The nature of innervation of unitary smooth muscles varies significantly in different organs. In many cases, the nerve endings are concentrated in those areas of the muscle where the pacemaker cells are located. The activity of the entire muscle can be regulated by changes in the frequency of pacemaker cell action potentials.
Another feature of unitary smooth muscle is that its fibers often contract in response to stretching. Contractions occur when the walls of many hollow organs (for example, the uterus) are stretched, when the volume of their internal contents increases.
Examples of unitary smooth muscles: muscles of the walls of the gastrointestinal tract, uterus, thin blood vessels.
Multiunitary smooth muscles
There are few multiunit smooth muscles between the cells gap junction each fiber acts independently of its neighbors, and the muscle behaves as many independent elements. Multiunit smooth muscles are abundantly supplied with branching autonomic nerves (Fig. 4-20 B). The overall response of the entire muscle depends on the amount activated fibers and on the frequency of nerve impulses. Although incoming nerve impulses are accompanied by depolarization and contractile responses of the fibers, action potentials are generally not generated in multiunit smooth muscles. The contractile activity of multiunitary smooth muscles is enhanced or weakened as a result of the supply of hormones in the blood, but multiunitary smooth muscles do not contract when stretched. Examples of multiunitary smooth muscles: muscles in the walls of the bronchi and large arteries, etc.
It should be emphasized that most smooth muscles do not have the properties of exclusively unitary or multiunitary smooth muscles. In fact, there is a continuous variety of smooth muscles with different combinations of properties of each type; unitary smooth muscles and multiunitary smooth muscles are two extremes.
Rice. 4-20. Smooth muscle structure
Smooth muscle potentials
Some types of smooth muscle fibers generate action potentials spontaneously, in the absence of any neurogenic or hormonal influence. The resting potential of the plasma membrane of such fibers is not maintained at a constant level, but undergoes gradual depolarization until it reaches a threshold level and an action potential is generated. After repolarization of the membrane, depolarization begins again (Fig. 4-21), so that a series of action potentials occurs, causing tonic contractile activity. Spontaneous potential shifts that depolarize the membrane to a threshold level are called pacemaker potentials.(As shown in other chapters, some cardiac muscle fibers and some types of CNS neurons also have pacemaker potentials and can spontaneously generate action potentials in the absence of external stimuli.)
It is interesting that in smooth muscles capable of generating action potentials, Ca 2+ ions, and not Na+, serve as carriers of positive charges into the cell during the rising phase of the action potential, i.e. When the membrane is depolarized, voltage-gated calcium channels open, and action potentials in smooth muscle are calcium in nature rather than sodium.
Unlike striated muscle, in smooth muscle there is a cytoplasmic concentration
Ca 2+ tion may increase (or decrease) as a result gradual depolarizing (or hyperpolarizing) shifts in membrane potential, increasing (or decreasing) the number of open calcium channels in the plasma membrane.
What role does extracellular Ca 2+ play in electromechanical coupling? The plasma membrane of smooth muscle cells contains two types of calcium channels - voltage-gated and chemical-mediated. Since the concentration of Ca 2+ in the extracellular fluid is 10,000 times higher than in the cytoplasm, the opening of calcium channels in the plasma membrane is accompanied by the entry of Ca 2+ into the cell. Due to the small size of the fiber, the incoming Ca 2+ ions quickly reach intracellular binding sites by diffusion.
Another difference is that while in skeletal muscle a single action potential releases enough Ca 2+ to activate all of the fiber's cross-bridges, in smooth muscle only a subset of the cross-bridges are activated in response to most stimuli. That is why the smooth muscle fiber generates tension gradually as the cytoplasmic concentration of Ca 2+ changes. The greater the increase in Ca 2+ concentration, the greater the number of cross bridges that are activated and the greater the voltage generated.
Rice. 4-21. Electrical potentials of smooth muscles
Sources of calcium entry into the cytoplasm
The increase in the concentration of Ca 2+ in the cytoplasm, due to which the contraction of smooth muscle is initiated, is provided from two sources: (1) the sarcoplasmic reticulum and (2) the extracellular environment from which Ca 2+ enters the cell through calcium channels of the plasma membrane. The relative contribution of these two Ca 2+ sources varies among smooth muscles. Some of them are more dependent on the extracellular concentration of Ca 2+, others - on Ca 2+ deposited in the sarcoplasmic reticulum.
Sarcoplasmic reticulum smooth muscle
As for the sarcoplasmic reticulum, it is less developed in smooth muscle than in skeletal muscle, and does not have a specific organization that would correlate with the location of thick and thin filaments (Fig. 4-22 A). In addition, smooth muscle lacks T-tubules connected to the plasma membrane. Since the diameter of the smooth muscle fiber is small and contraction develops slowly, there is no functional need for rapid propagation of the excitatory signal deep into the fiber. At the same time, special structures are observed between areas of the plasma membrane and sarcoplasmic reticulum,
similar to the specialized contacts between the membranes of T-tubules and lateral sacs in striated fibers. These structures mediate the interface between the action potential of the plasma membrane and the release of Ca 2+ from the sarcoplasmic reticulum. Initiation of Ca 2+ release from regions of the sarcoplasmic reticulum located in the center of the fiber involves second messengers released by the plasma membrane or formed in the cytoplasm in response to the binding of extracellular chemical mediators to plasma membrane receptors (Fig. 4-22 B).
In some smooth muscles, the Ca 2+ concentration is sufficient to maintain cross-bridge activity at a certain low level even in the absence of external stimuli. This phenomenon is called smooth muscle tone. The intensity of the tone is changed by factors affecting the cytoplasmic concentration of Ca 2+.
Removal of Ca 2+ from the cytoplasm, necessary for the fiber to relax, occurs through active transport of Ca 2+ back into the sarcoplasmic reticulum and also across the plasma membrane into the extracellular environment. The rate of Ca 2+ removal in smooth muscle is much lower than in skeletal muscle. Hence the different duration of a single contraction - a few seconds for smooth muscle and a fraction of a second for skeletal muscle.
The mechanisms of calcium metabolism are presented in
rice. 4-22 G.
Rice. 4-22. Sarcoplasmic reticulum of smooth muscles.
A - structure of the sarcoplasmic reticulum. B - sources of calcium intake through ion channels. B - sources of calcium through pumps and exchangers
Smooth muscle contractions
In the cytoplasm of smooth muscle fibers there are two types of filaments: thick myosin-containing and thin actin-containing. Thin filaments are attached either to the plasma membrane or to cytoplasmic structures - the so-called dense corpuscles(functional analogues of the Z-bands of striated fibers). In relaxed smooth muscle fiber, filaments of both types are oriented at an oblique angle to the long axis of the cell. During fiber shortening, areas of the plasma membrane located between the actin attachment points bulge. Thick and thin filaments are not combined into myofibrils, as in striated muscles, and do not form regularly repeating sarcomeres, so cross-striations are not observed. However, smooth muscle contraction occurs through a sliding filament mechanism.
The myosin concentration in smooth muscle is only about one-third that of striated muscle, while the actin content can be twice as high. Despite these differences, the maximum tension per unit cross-sectional area developed by smooth and skeletal muscles is similar.
The relationship between isometric tension and length for smooth muscle fibers is quantitatively the same as for skeletal muscle fibers. At the optimal fiber length, maximum stress develops, and when the length shifts in both directions from its optimal value, the stress decreases. However, smooth muscle, compared to skeletal muscle, is capable of developing tension over a wider range of lengths. This is an important adaptive property, given that most smooth muscles are part of the walls of hollow organs, and when the volume changes, the length of the muscle fibers also changes. Even with relatively high magnification volume, as, for example, when filling the bladder, the smooth muscle fibers in its walls retain, to a certain extent, the ability to develop tension; in striated fibers, such stretching could cause the thick and thin filaments to diverge beyond their overlap zone.
As in striated muscle, contractile activity in smooth muscle fibers is regulated by changes in the cytoplasmic concentration of Ca 2+ ions. However, these two muscle types differ significantly in the mechanism by which Ca 2+ influences cross-bridge activity and changes in Ca 2+ concentration in response to stimulation.
Rice. 4-23. In smooth muscle, thick and thin filaments are oriented at an angle to the fiber axes and are attached to the plasma membrane or to dense bodies in the cytoplasm. When muscle cells are activated, thick and thin filaments slide past each other so that the cells shorten and thicken
Activation of cross bridges
Smooth muscle thin filaments do not contain the Ca 2+ binding protein troponin C, which mediates the Ca 2+ triggering role of cross-bridge activity in skeletal muscle and the myocardium. Instead, the smooth muscle cross-bridge cycle is controlled by a Ca 2+ -regulated myosin phosphorylating enzyme. Only the phosphorylated form of myosin in smooth muscle can bind to actin and mediate cycles of cross-bridge movements.
Let us consider the process of smooth muscle contraction in detail. An increase in the level of Ca 2+ in the cytoplasm initiates a slow chain of events leading, on the one hand, to the release of the active myosin binding site on actin and, on the other hand, to an increase in the activity of myosin ATPase, and without this increase in the activity of myosin ATPase in smooth muscle contraction can't start.
The first phase of the myosin head activation process involves the binding of 4 Ca 2+ ions to calmodulin(CaM), which in this sense is very similar to troponin C of striated muscle. Next, the Ca 2+ -CaM complex activates an enzyme called myosin light chain kinase(KLTSM) (myosin light chain kinase, MLCK). MLCK contains an ATP-binding domain and an active site that transfers phosphate from ATP to the acceptor protein. By this mechanism, MLCK, in turn, phosphorylates the light regulatory chain associated with the head of the myosin II molecule. Phosphorylation of the light chain changes the conformation of the myosin II head, which is sufficiently altered by an increase in its ATPase activity to allow it to interact with actin. That is, the system works like a molecular motor (Fig. 4-23 A).
Figure 4-23 B shows two independent cascades leading to smooth muscle contraction. Cascade (1) includes a mechanism for releasing the blocking of the active center of actin, which myosin must contact. Cascade (2) includes the activation mechanism of the myosin head. The result of these two cascades is the formation of the actomyosin complex.
Let us consider the first cascade of release from blocking the active center of actin. Two proteins, caldesmon and calpomin, block the ability of actin to bind to myosin. Both are Ca 2+ -CaM binding proteins, and both bind actin. On the one hand, Ca 2+ binds to CaM, and the Ca 2+ -CaM complex has a dual effect on calponin. The first effect is that the Ca 2+ -CaM complex binds to calponin. The second effect is that the Ca 2+ -CaM complex activates Ca 2+ -CaM-dependent protein kinase, which phosphorylates calponin. Both effects reduce calponin ATPase inhibition
myosin activity. Caldesmon also inhibits the ATPase activity of smooth muscle myosin. On the other hand, Ca 2+ binds to CaM, and the Ca 2+ -CaM complex binds through Pi to caldesmon, which shifts the latter from the actin-myosin binding center. The binding site on actin opens.
Consider the second cascade, which is presented in panel A. The first phase of the myosin head activation process involves the binding of four Ca 2+ ions to CaM. The formed Ca 2+ -CaM complex activates MLCK. MLCK phosphorylates the light regulatory chain associated with the head of the myosin II molecule. Phosphorylation of the light chain changes the conformation of the myosin II head, which is sufficiently altered by an increase in its ATPase activity to allow it to interact with actin.
As a result, the actomyosin complex is formed.
The smooth muscle isoform of myosin ATPase has a very low maximum activity, approximately 10-100 times lower than the activity of skeletal muscle myosin ATPase. Since the rate of cyclic movements of cross bridges and, accordingly, the rate of shortening depend on the rate of ATP hydrolysis, smooth muscle contracts much more slowly than skeletal muscle. In addition, smooth muscle does not fatigue during prolonged activity.
In order for smooth muscle to relax after contraction, dephosphorylation of myosin is necessary, since dephosphorylated myosin cannot be associated with actin. This process is catalyzed by myosin light chain phosphatase, which is active during the entire time of rest and contraction of smooth muscle. With an increase in the cytoplasmic Ca 2+ concentration, the rate of myosin phosphorylation by active kinase becomes higher than the rate of its dephosphorylation by phosphatase, and the amount of phosphorylated myosin in the cell increases, ensuring the development of tension. When the cytoplasmic Ca 2+ concentration decreases, the rate of dephosphorylation becomes higher than the rate of phosphorylation, the amount of phosphorylated myosin falls, and the smooth muscle relaxes.
When saving higher level of cytoplasmic Ca 2+, the rate of ATP hydrolysis by myosin cross bridges decreases, despite the persistence of isometric tension. If a phosphorylated cross-bridge attached to actin undergoes dephosphorylation, it will be in a state of persistent rigid tension, remaining immobile. When such dephosphorylated cross-bridges bind to ATP, they dissociate from actin much more slowly. This ensures the ability of smooth muscle to maintain tension for a long time with low ATP consumption.
Smooth muscle are presented in the walls of the digestive canal, bronchi, blood and lymphatic vessels, bladder, uterus, as well as in the iris, ciliary muscle, skin and glands. Unlike striated muscles, they are not separate muscles, but form only part of the organs. Smooth muscle cells have an elongated spindle- or ribbon-like shape with pointed ends. Their length in humans is usually about 20 microns. Smooth muscle cells reach the greatest length (up to 500 microns) in the wall of the pregnant human uterus. In the middle part of the cell there is a rod-shaped nucleus, and in the cytoplasm along the entire cell, thin, completely homogeneous myofibrils run parallel to each other. Therefore, the cell does not have transverse striations. Thicker myofibrils are located in the outer layers of the cell. They are called boundary and have uniaxial birefringence. An electron microscope shows that myofibrils are bundles of protofibrils and have cross-striations that are not visible in a light microscope. Smooth muscle cells can regenerate by division (mitosis). They contain a type of actomyosin - tonoactomyosin. Between smooth muscle cells there are the same areas of membrane contact, or nexuses, as between cardiac ones, along which excitation and inhibition are supposed to spread from one smooth muscle cell to another.
In smooth muscles, excitation spreads slowly. Contractions of smooth muscles are caused by stronger and longer-lasting stimuli than skeletal muscles. The latent period of its contraction lasts several seconds. Smooth muscles contract much slower than skeletal muscles. Thus, the period of contraction of smooth muscle in the stomach of a frog is 15-20 s. Smooth muscle contractions can last for many minutes or even hours. Unlike skeletal muscles, smooth muscle contractions are tonic. Smooth muscles are capable of being in a state of tonic tension for a long time with an extremely low expenditure of substances and energy. For example, the smooth muscles of the sphincters of the digestive canal, bladder, gall bladder, uterus and other organs are in good shape for tens of minutes and many hours. The smooth muscles of the walls of the blood vessels of higher vertebrates remain in good shape throughout life.
There is a direct relationship between the frequency of impulses arising in the muscle and the level of its tension. The higher the frequency, the greater the tone up to a certain limit due to the summation of stresses of non-simultaneously tense muscle fibers.
Smooth muscles have tasticity - the ability to maintain their length when stretched without changing tension, unlike skeletal muscles, which are tense when stretched.
Unlike skeletal muscles, many smooth muscles exhibit automaticity. They contract under the influence of local reflex mechanisms, for example the Meissner and Auerbach plexuses in the digestive canal, or chemical substances, entering the blood, such as acetylcholine, norepinephrine and adrenaline. Automatic contractions of smooth muscles are enhanced or inhibited under the influence of nerve impulses coming from the nervous system. Therefore, unlike skeletal muscles, there are special inhibitory nerves that stop contraction and cause relaxation of smooth muscles. Some smooth muscles that have a large number of nerve endings do not have automaticity, for example, the sphincter of the pupil, the nictitating membrane of a cat.
Smooth muscles can shorten greatly, much more than skeletal muscles. A single stimulation can cause smooth muscle contraction by 45%, and the maximum contraction with a frequent rhythm of stimulation can reach 60-75%.
Smooth muscle tissue also develops from mesoderm (arises from mesenchyme); it consists of individual, highly elongated spindle-shaped cells, much smaller in size compared to the fibers of striated muscles. Their length ranges from 20 to 500 μ, and their width from 4 to 7 μ. As a rule, these cells have one elongated nucleus lying in the center of the cell. In the protoplasm of the cell, numerous and very thin myofibrils pass in the longitudinal direction, which do not have transverse striations and are completely invisible without special treatment. Each smooth muscle cell is covered with a thin connective tissue membrane. These membranes connect neighboring cells to each other. In contrast to striated fibers, located almost the entire length of the skeletal muscle, throughout any smooth muscle complex there is a significant number of cells located in one line.
Smooth muscle cells are found in the body either scattered singly in connective tissue or associated in muscle complexes of various sizes.
In the latter case, each muscle cell is also surrounded on all sides by intercellular substance, penetrated by the finest fibrils, the number of which can be very different. The finest networks of elastic fibers are also found in the intercellular substance.
Smooth muscle cells of organs are united into muscle bundles. In many cases (urinary tract, uterus, etc.), these bundles branch and merge with other bundles, forming surface networks of varying densities. If a large number of bundles are located closely, then a dense muscular layer is formed (for example, the gastrointestinal tract). The blood supply to smooth muscles is carried out through vessels that pass through large connective tissue layers between the bundles; capillaries penetrate between the fibers of each bundle and, branching along it, form a dense capillary network. Smooth muscle tissue also contains lymphatic vessels. Smooth muscles are innervated by fibers of the autonomic nervous system. Smooth muscle cells, unlike striated muscle fibers, produce slow, sustained contractions. They are able to work for a long time and with great strength. For example, the muscular walls of the uterus during childbirth, which lasts for hours, develop a force that is inaccessible to striated muscles. The activity of smooth muscles, as a rule, is not subject to our will (vegetative innervation, see below) - they are involuntary.
Smooth muscle in its development (phylogeny) is more ancient than striated muscle, and is more common in the lower forms of the animal world.
Classification of smooth muscles
Smooth muscles are divided into visceral (unitary) and multiunitary. Visceral smooth muscles are found in all internal organs, ducts of the digestive glands, blood and lymphatic vessels, and skin. Mulipunitary muscles include the ciliary muscle and the iris muscle. The division of smooth muscles into visceral and multiunitary is based on the different densities of their motor innervation. In visceral smooth muscle, motor nerve endings are present on a small number of smooth muscle cells. Despite this, excitation from the nerve endings is transmitted to all smooth muscle cells of the bundle due to tight contacts between neighboring myocytes - nexuses. Nexes allow action potentials and slow waves of depolarization to propagate from one muscle cell to another, so visceral smooth muscles contract simultaneously with the arrival of a nerve impulse.
Functions and properties of smooth muscles
Plastic. Another important specific characteristic of smooth muscle is the variability of tension without a regular connection with its length. Thus, if visceral smooth muscle is stretched, its tension will increase, but if the muscle is held in the state of elongation caused by stretching, then the tension will gradually decrease, sometimes not only to the level that existed before the stretch, but also below this level. This property is called smooth muscle plasticity. Thus, smooth muscle is more similar to a viscous plastic mass than to a poorly pliable structured tissue. The plasticity of smooth muscles contributes to the normal functioning of internal hollow organs.
Relationship between excitation and contraction. It is more difficult to study the relationship between electrical and mechanical manifestations in visceral smooth muscle than in skeletal or cardiac muscle, since visceral smooth muscle is in a state of continuous activity. Under conditions of relative rest, a single AP can be recorded. The contraction of both skeletal and smooth muscle is based on the sliding of actin in relation to myosin, where the Ca2+ ion performs a trigger function.
The mechanism of contraction of smooth muscle has a feature that distinguishes it from the mechanism of contraction of skeletal muscle. This feature is that before smooth muscle myosin can exhibit its ATPase activity, it must be phosphorylated. Phosphorylation and dephosphorylation of myosin is also observed in skeletal muscle, but in it the phosphorylation process is not necessary to activate the ATPase activity of myosin. The mechanism of phosphorylation of smooth muscle myosin is as follows: the Ca2+ ion combines with calmodulin (calmodulin is a receptive protein for the Ca2+ ion). The resulting complex activates the enzyme, myosin light chain kinase, which in turn catalyzes the process of myosin phosphorylation. Actin then slides against myosin, which forms the basis of contraction. Note that the trigger for smooth muscle contraction is the addition of Ca2+ ion to calmodulin, while in skeletal and cardiac muscle the trigger is the addition of Ca2+ to troponin.
Chemical sensitivity. Smooth muscles are highly sensitive to various physiologically active substances: adrenaline, norepinephrine, ACh, histamine, etc. This is due to the presence of specific receptors on the smooth muscle cell membrane. If you add adrenaline or norepinephrine to a preparation of intestinal smooth muscle, the membrane potential increases, the frequency of AP decreases and the muscle relaxes, i.e., the same effect is observed as when the sympathetic nerves are excited.
Norepinephrine acts on α- and β-adrenergic receptors on the smooth muscle cell membrane. The interaction of norepinephrine with β-receptors reduces muscle tone as a result of activation of adenylate cyclase and the formation of cyclic AMP and a subsequent increase in the binding of intracellular Ca2+. The effect of norepinephrine on α-receptors inhibits contraction by increasing the release of Ca2+ ions from muscle cells.
ACh has an effect on membrane potential and contraction of intestinal smooth muscle that is opposite to the effect of norepinephrine. The addition of ACh to an intestinal smooth muscle preparation reduces membrane potential and increases the frequency of spontaneous APs. As a result, the tone increases and the frequency of rhythmic contractions increases, i.e., the same effect is observed as when the parasympathetic nerves are excited. ACh depolarizes the membrane and increases its permeability to Na+ and Ca+.
The smooth muscles of some organs respond to various hormones. Thus, the smooth muscles of the uterus in animals during the periods between ovulation and when the ovaries are removed are relatively inexcitable. During estrus or in ovarian animals that have been given estrogen, smooth muscle excitability increases. Progesterone increases membrane potential even more than estrogen, but in this case the electrical and contractile activity of the uterine muscles is inhibited.
Smooth muscles are part of the internal organs. Thanks to contraction, they provide the motor function of their organs (digestive canal, genitourinary system, blood vessels, etc.). Unlike skeletal muscles, smooth muscles are involuntary.
Morpho-functional structure of smooth muscles. The main structural unit of smooth muscle is the muscle cell, which has a spindle-shaped shape and is covered on the outside with a plasma membrane. Under an electron microscope, numerous depressions can be seen in the membrane - caveolae, which significantly increase the total surface of the muscle cell. The sarcolemma of a muscle cell includes a plasma membrane along with the basement membrane, which covers it from the outside, and adjacent collagen fibers. The main intracellular elements: nucleus, mitochondria, lysosomes, microtubules, sarcoplasmic reticulum and contractile proteins.
Muscle cells form muscle bundles and muscle layers. The intercellular space (100 nm or more) is filled with elastic and collagen fibers, capillaries, fibroblasts, etc. In some areas, the membranes of neighboring cells lie very tightly (the gap between cells is 2-3 nm). It is assumed that these areas (nexus) serve for intercellular communication and transmission of excitation. It has been proven that some smooth muscles contain a large number of nexus (pupillary sphincter, circular muscles of the small intestine, etc.), while others have little or no nexus (vas deferens, longitudinal muscles of the intestines). There is also an intermediate, or desmopodibny, connection between non-skinned muscle cells (through thickening of the membrane and with the help of cell processes). Obviously, these connections are important for the mechanical connection of cells and the transmission of mechanical force by cells.
Due to the chaotic distribution of myosin and actin protofibrils, smooth muscle cells are not striated, like skeletal and cardiac cells. Unlike skeletal muscles, smooth muscles do not have a T-system, and the sarcoplasmic reticulum makes up only 2-7% of the myoplasm volume and has no connections with the external environment of the cell.
Physiological properties of smooth muscles .
Smooth muscle cells, like striated ones, contract due to the sliding of actin protofibrils between myosin protofibrils, but the speed of sliding and hydrolysis of ATP, and therefore the speed of contraction, is 100-1000 times less than in striated muscles. Thanks to this, smooth muscles are well adapted for long-term gliding with little energy expenditure and without fatigue.
Smooth muscles, taking into account the ability to generate AP in response to threshold or supra-horn stimulation, are conventionally divided into phasic and tonic. Phasic muscles generate a full-fledged potential action, while tonic muscles generate only a local one, although they also have a mechanism for generating full-fledged potentials. The inability of tonic muscles to perform AP is explained by the high potassium permeability of the membrane, which prevents the development of regenerative depolarization.
The value of the membrane potential of smooth muscle cells of non-skinned muscles varies from -50 to -60 mV. As in other muscles, including nerve cells, mainly +, Na +, Cl- take part in its formation. In the smooth muscle cells of the digestive canal, uterus, and some vessels, the membrane potential is unstable; spontaneous fluctuations are observed in the form of slow waves of depolarization, at the top of which AP discharges may appear. The duration of smooth muscle action potential ranges from 20-25 ms to 1 s or more (for example, in the muscles of the bladder), i.e. it is longer than the duration of skeletal muscle AP. In the mechanism of action of smooth muscles, next to Na +, Ca2 + plays an important role.
Spontaneous myogenic activity. Unlike skeletal muscles, smooth muscles of the stomach, intestines, uterus, and ureters have spontaneous myogenic activity, i.e. develop spontaneous tetanohyodine contractions. They are stored under conditions of isolation of these muscles and with pharmacological switching off of the intrafusal nerve plexuses. So, AP occurs in the smooth muscles themselves, and is not caused by the transmission of nerve impulses to the muscles.
This spontaneous activity is of myogenic origin and occurs in muscle cells that function as a pacemaker. In these cells, the local potential reaches a critical level and passes into AP. But after membrane repolarization, a new local potential spontaneously arises, which causes another AP, etc. The AP, spreading through the nexus to neighboring muscle cells at a speed of 0.05-0.1 m/s, covers the entire muscle, causing its contraction. For example, peristaltic contractions of the stomach occur with a frequency of 3 times per 1 minute, segmental and pendulum-like movements of the colon - 20 times per 1 minute in the upper sections and 5-10 per 1 minute in the lower sections. Thus, the smooth muscle fibers of these internal organs have automaticity, which is manifested by their ability to contract rhythmically in the absence of external stimuli.
What is the reason for the appearance of potential in pacemaker smooth muscle cells? Obviously, it occurs due to a decrease in potassium and an increase in sodium and calcium permeability of the membrane. As for the regular occurrence of slow waves of depolarization, most pronounced in the muscles of the gastrointestinal tract, there is no reliable data on their ionic origin. Perhaps a certain role is played by a decrease in the initial inactivating component of the potassium current during depolarization of muscle cells due to inactivation of the corresponding potassium ion channels.
Elasticity and extensibility of smooth muscles. Unlike skeletal muscles, smooth muscles act as plastic, elastic structures when stretched. Thanks to plasticity, smooth muscle can be completely relaxed in both contracted and stretched states. For example, the plasticity of the smooth muscles of the wall of the stomach or bladder as these organs fill prevents an increase in intracavitary pressure. Excessive stretching often leads to stimulation of contraction, which is caused by the depolarization of pacemaker cells that occurs when the muscle is stretched, and is accompanied by an increase in the frequency of action potential, and as a result, an increase in contraction. Contraction, which activates the stretching process, plays a large role in the self-regulation of the basal tone of blood vessels.
The mechanism of smooth muscle contraction. A prerequisite for the occurrence is a contraction of smooth muscles, as well as skeletal muscles, and an increase in the concentration of Ca2 + in the myoplasm (up to 10-5 M). It is believed that the contraction process is activated primarily by extracellular Ca2+, which enters muscle cells through voltage-gated Ca2+ channels.
The peculiarity of neuromuscular transmission in smooth muscles is that innervation is carried out by the autonomic nervous system and it can have both an excitatory and an inhibitory effect. By type, there are cholinergic (mediator acetylcholine) and adrenergic (mediator norepinephrine) mediators. The former are usually found in the muscles of the digestive system, the latter in the muscles of the blood vessels.
The same transmitter in some synapses can be excitatory, and in others - inhibitory (depending on the properties of the cytoreceptors). Adrenergic receptors are divided into a- and b-. Norepinephrine, acting on α-adrenergic receptors, constricts blood vessels and inhibits the motility of the digestive tract, and acting on B-adrenergic receptors, stimulates the activity of the heart and dilates the blood vessels of some organs, relaxes the muscles of the bronchi. Described neuromuscular-. transmission in smooth muscles for the help of other mediators.
In response to the action of an excitatory transmitter, depolarization of smooth muscle cells occurs, which manifests itself in the form of an excitatory synaptic potential (ESP). When it reaches a critical level, PD occurs. This happens when several impulses approach the nerve ending one after another. The occurrence of PGI is a consequence of an increase in the permeability of the postsynaptic membrane for Na +, Ca2 + and SI."
The inhibitory transmitter causes hyperpolarization of the postsynaptic membrane, which is manifested in the inhibitory synaptic potential (ISP). Hyperpolarization is based on an increase in membrane permeability, mainly for K +. The role of inhibitory mediator in smooth muscles excited by acetylcholine (for example, muscles of the intestine, bronchi) is played by norepinephrine, and in smooth muscles for which norepinephrine is an excitatory mediator (for example, muscles of the bladder), acetylcholine plays the role.
Clinical and physiological aspect. In some diseases, when the innervation of skeletal muscles is disrupted, their passive stretching or displacement is accompanied by a reflex increase in their tone, i.e. resistance to stretching (spasticity or rigidity).
If blood circulation is impaired, as well as under the influence of certain metabolic products (lactic and phosphoric acids), toxic substances, alcohol, fatigue, or a decrease in muscle temperature (for example, during prolonged swimming in cold water), contracture may occur after prolonged active muscle contraction. The more the muscle function is impaired, the more pronounced the contracture aftereffect is (for example, contracture of the masticatory muscles in pathology of the maxillofacial region). What is the origin of contracture? It is believed that the contracture arose due to a decrease in the concentration of ATP in the muscle, which led to the formation of a permanent connection between the cross bridges and actin protofibrils. In this case, the muscle loses flexibility and becomes hard. The contracture goes away and the muscle relaxes when the ATP concentration reaches normal levels.
In diseases such as myotonia, muscle cell membranes are excited so easily that even a slight irritation (for example, the introduction of a needle electrode during electromyography) causes the discharge of muscle impulses. Spontaneous APs (fibrillation potentials) are also recorded at the first stage after denervation of the muscle (until inaction leads to its atrophy).
Smooth muscle is a contractile tissue consisting of individual cells and without transverse striations (Fig. 1.). The smooth muscle cell has a spindle-shaped shape, approximately 50 - 400 µm in length and 2-10 µm in thickness. Individual threads are connected by special intercellular contacts - desmosomes and form a network with collagen fibers woven into it. The lack of cross-striations characteristic of cardiac and skeletal muscles is explained by the irregular distribution of myosin and actin filaments. Smooth muscles also shorten due to the sliding of myofilaments relative to each other, but the speed of sliding and the breakdown of ATP here is 100 - 1000 times lower than that of striated muscles. In this regard, smooth muscles are especially well adapted for long-term sustainable contraction, which does not lead to fatigue and significant energy consumption.
Smooth muscles are part of internal organs, blood vessels and skin. They are distinguished by the presence of interesting functional features: the ability to carry out relatively slow movements and prolonged tonic contractions. Slow movements (contractions), often having a rhythmic contraction of the smooth muscles of the walls of hollow organs: the stomach, intestines, ducts of the digestive glands, bladder, gall bladder, ensure the movement of the contents of these organs. An example is the pendular and peristaltic movements of the intestines. Prolonged tonic contractions of smooth muscles are especially pronounced in the sphincters of hollow organs; their tonic contractions prevent the release of contents. This ensures the presence of bile in the gallbladder and urine in the bladder, and the formation of feces in the large intestine.
Shows the structure (left) of striated and smooth muscles in vertebrates and the relationship between electrical (solid lines) and mechanical (dashed lines) activity (right). A. Striated muscles are multinucleated cylindrical cells. They generate fast action potentials and fast contractions. B. Smooth muscle fibers have one core, small size and fusiform shape. They are connected to each other by their lateral surfaces through gap junctions and form electrically united groups of cells.
The innervation is diffuse, the activation of the fibers is carried out due to the release of the mediator from the extensions located along the autonomic nerve. Although smooth muscle cell action potentials are fast, the resulting contractions are slow and long-lasting.
The thin smooth muscles of the walls of blood vessels, especially arteries and arterioles, are in a state of constant tonic contraction. The tone of the muscle layer of the artery walls regulates blood pressure and blood supply to organs.
Motor innervation of smooth muscles is carried out by processes of cells of the autonomic nervous system, sensitive - by processes of cells of sympathetic ganglia. The tone and motor function of smooth muscles are also regulated by humoral influences.
All smooth muscles can be divided into two groups:
1. Smooth muscles with myogenic activity. In many intestinal smooth muscles (eg, the cecum), a single contraction caused by an action potential lasts several seconds. Consequently, contractions that follow with an interval of less than 2 s overlap each other, and at a frequency above 1 Hz they merge into a more or less smooth tetanus (tetan-like tone) (Fig. 2). The nature of such tetanus is myogenic; Unlike skeletal muscle, smooth muscles of the intestine, ureter, stomach and uterus are capable of spontaneous thetan-like contractions after isolation and denervation and even with blockade of intramural ganglion neurons. Consequently, their action potentials are not caused by the transmission of nerve impulses to the muscle, but are of myogenic origin.
Myogenic excitation occurs in pacemaker cells, which are identical to other muscle cells in structure, but differ in electrophysiological properties. Pacemaker potentials depolarize the membrane to a threshold level, causing an action potential. Due to the entry of cations into the cell (mainly Ca2+), the membrane depolarizes to zero level and even changes polarity to +20 mV for a few milliseconds. After repolarization, a new pacemaker potential follows, ensuring the generation of the next action potential. When a colon preparation is exposed to acetylcholine, pacemaker cells depolarize to a near-threshold level, and the frequency of action potentials increases. The contractions they cause merge to an almost smooth tetanus. The higher the frequency of action potentials, the more united the tetanus and the stronger the contraction resulting from the summation of single contractions. Conversely, application of norepinephrine to the same preparation forms a hyperpolar membrane and, as a result, reduces the frequency of action potentials and the magnitude of tetanus. These are the mechanisms of modulation of the spontaneous activity of pacemakers by the autonomic nervous system and its mediators.
Fig.2.
Treatment with acetylcholine (arrow) increases the frequency of action potentials so that single beats coalesce into tetanus. The bottom record is the time course of muscle tension.
2. Smooth muscles without myogenic activity. Unlike the intestinal muscles, the smooth muscles of the arteries, seminal ducts, iris, and ciliary muscles usually have little or no spontaneous activity. Their contraction occurs under the influence of impulses supplied to these muscles via the autonomic nerves. Such features are due to the structural organization of their tissue. Although the cells in it are electrically connected by nexuses, many of them form direct synaptic contacts with the axons innervating them, but do not form the usual neuromuscular synapses in smooth muscle tissue. The release of the transmitter occurs from numerous thickenings (extensions) located along the length of the autonomic axons (Fig. 1).
Mediators reach muscle cells through diffusion and activate them. At the same time, excitatory potentials arise in the cells, turning into action potentials that cause a tetanic contraction.
Functions and properties of smooth muscles
Electrical activity. Visceral smooth muscles are characterized by unstable membrane potential. Fluctuations in membrane potential, regardless of nervous influences, cause irregular contractions that maintain the muscle in a state of constant partial contraction - tone. The tone of smooth muscles is clearly expressed in the sphincters of hollow organs: the gall bladder, bladder, at the junction of the stomach into the duodenum and the small intestine into the large intestine, as well as in the smooth muscles of small arteries and arterioles. The membrane potential of smooth muscle cells does not reflect the true value of the resting potential. When the membrane potential decreases, the muscle contracts, and when the membrane potential increases, it relaxes.
Automation. The action potentials of smooth muscle cells are autorhythmic (pacemaker) in nature, similar to the potentials of the conduction system of the heart. Pacemaker potentials are recorded in various areas of smooth muscle. This indicates that any visceral smooth muscle cells are capable of spontaneous automatic activity. Automaticity of smooth muscles, i.e. the ability for automatic (spontaneous) activity is inherent in many internal organs and vessels.
Tensile response. A unique feature of visceral smooth muscle is its response to stretch. In response to stretch, smooth muscle contracts. This is due to the fact that stretching reduces the membrane potential of cells, increases the frequency of AP and, ultimately, the tone of smooth muscles. In the human body, this property of smooth muscles serves as one of the ways to regulate the motor activity of internal organs. For example, when the stomach is filled, its wall stretches. An increase in the tone of the stomach wall in response to its stretching helps maintain the volume of the organ and better contact of its walls with incoming food. In blood vessels, distension created by fluctuations in blood pressure is a major factor in the myogenic self-regulation of vascular tone. Finally, stretching of the uterine muscles by the growing fetus is one of the reasons for the onset of labor.
Plastic. Another important specific characteristic of smooth muscle is the variability of tension without a regular connection with its length. Thus, if visceral smooth muscle is stretched, its tension will increase, but if the muscle is held in the state of elongation caused by stretching, then the tension will gradually decrease, sometimes not only to the level that existed before the stretch, but also below this level. This property is called smooth muscle plasticity. Thus, smooth muscle is more similar to a viscous plastic mass than to a poorly pliable structured tissue. The plasticity of smooth muscles contributes to the normal functioning of internal hollow organs.
Relationship between excitation and contraction. It is more difficult to study the relationship between electrical and mechanical manifestations in visceral smooth muscle than in skeletal or cardiac muscle, since visceral smooth muscle is in a state of continuous activity. Under conditions of relative rest, a single AP can be recorded. The contraction of both skeletal and smooth muscle is based on the sliding of actin in relation to myosin, where the Ca2+ ion performs a trigger function.
The mechanism of contraction of smooth muscle has a feature that distinguishes it from the mechanism of contraction of skeletal muscle. This feature is that before smooth muscle myosin can exhibit its ATPase activity, it must be phosphorylated. Phosphorylation and dephosphorylation of myosin is also observed in skeletal muscle, but in it the phosphorylation process is not necessary to activate the ATPase activity of myosin.
Chemical sensitivity. Smooth muscles are highly sensitive to various physiologically active substances: adrenaline, norepinephrine, ACh, histamine, etc. This is due to the presence of specific receptors on the smooth muscle cell membrane. If you add adrenaline or norepinephrine to a preparation of intestinal smooth muscle, the membrane potential increases, the frequency of AP decreases and the muscle relaxes, i.e., the same effect is observed as when the sympathetic nerves are excited.
Norepinephrine acts on b- and b-adrenergic receptors of the membrane of smooth muscle cells. The interaction of norepinephrine with β-receptors reduces muscle tone as a result of activation of adenylate cyclase and the formation of cyclic AMP and a subsequent increase in the binding of intracellular Ca2+. The effect of norepinephrine on β-receptors inhibits contraction by increasing the release of Ca2+ ions from muscle cells.
ACh has an effect on membrane potential and contraction of intestinal smooth muscle that is opposite to the effect of norepinephrine. The addition of ACh to an intestinal smooth muscle preparation reduces membrane potential and increases the frequency of spontaneous APs. As a result, the tone increases and the frequency of rhythmic contractions increases, i.e., the same effect is observed as when the parasympathetic nerves are excited. ACh depolarizes the membrane and increases its permeability to Na+ and Ca+.
The smooth muscles of some organs respond to various hormones. Thus, the smooth muscles of the uterus in animals during the periods between ovulation and when the ovaries are removed are relatively inexcitable. During estrus or in ovarian animals that have been given estrogen, smooth muscle excitability increases. Progesterone increases membrane potential even more than estrogen, but in this case the electrical and contractile activity of the uterine muscles is inhibited.
As in skeletal muscle, trigger stimulates contraction of most smooth muscles is an increase in the amount of intracellular calcium ions. In different types of smooth muscle, this increase can be caused by neural stimulation, hormonal stimulation, fiber stretch, or even a change in the chemical composition of the environment surrounding the fiber.
However, in smooth muscles lack troponin(a regulatory protein that is activated by calcium). Smooth muscle contraction is activated by a completely different mechanism, outlined below.
The combination of calcium ions with calmodulin. Activation of myosin kinase and phosphorylation of the myosin head.
Instead of troponin smooth muscle cells contain large amounts of another regulatory protein called calmodulin. Although this protein is similar to troponin, it differs in the way it triggers contraction. Calmodulin does this by activating myosin cross bridges. Activation and reduction are carried out in the following sequence.
1. Calcium ions bind to calmodulin.
2. The calmodulin-calcium complex binds to the phosphorylating enzyme myosin kinase and activates it.
3. One of the light chains of each myosin head, called the regulatory chain, is phosphorylated by myosin kinase. When this chain is not phosphorylated, cyclic attachment and detachment of the myosin head with respect to the actin filament does not occur. But when the regulatory chain is phosphorylated, the head acquires the ability to re-bind with the actin filament and carry out the entire cyclic process of periodic “pull-ups” that underlie contraction, as in skeletal muscle.
Stopping the reduction. The role of myosin phosphatase. When the concentration of calcium ions falls below a critical level, the above processes automatically develop in the opposite direction, except for phosphorylation of the myosin head. To reverse the development of this condition, another enzyme is needed - myosin phosphatase, which is localized in the fluids of the smooth muscle cell and cleaves the phosphatase from the regulatory light chain. After this, cyclic activity, and therefore contraction, stops.
Therefore, the time necessary for muscle relaxation, is largely determined by the amount of active myosin phosphatase in the cell.
Possible mechanism for regulating the “latch” mechanism. Due to the importance of the latch mechanism in smooth muscle function, attempts are being made to explain this phenomenon, since it makes it possible to maintain long-term smooth muscle tone in many organs without significant energy expenditure. Among the many proposed mechanisms, we present one of the simplest.
When strongly activated and myosin kinase, and myosin phosphatase, the cycle frequency of myosin heads and the contraction speed are high. Then, as enzyme activation decreases, the cycle frequency decreases, but at the same time, the deactivation of these enzymes allows the myosin heads to remain attached to the actin filaments for increasingly longer portions of the cycle. Consequently, the number of heads attached to the actin filament at any given time remains large.
Since the number heads attached to actin determines the static force of the contraction, the tension is held, or "latched". However, little energy is used, since ATP is not broken down into ADP, except in rare cases when a head is disconnected.
Muscle tissue
Efferent innervation smooth muscle tissue is carried out by both the sympathetic (noradrenergic innervation) and parasympathetic (cholinergic innervation) parts of the autonomic nervous system, which have the opposite effect on the contractile activity of muscle tissue. Its serotonergic and peptidergic innervation has also been described. Nerve endings are found only on individual cells and have the appearance of varicose areas of thin branches of axons. Excitation is transmitted to neighboring myocytes via gap junctions.
Afferent innervation is provided by branches of nerve fibers that form free endings in smooth muscle tissue.
Humoral regulation of smooth muscle tissue activity. Hormones and other biologically active substances influence the contractile activity of smooth muscle tissue (different in different organs) due to the presence of corresponding sets of receptors on its cells. These substances include histamine, serotonin, bradykinin, endothelin, nitric oxide, leukotrienes, prostaglandins, neurotensin, substance P, cholecystokinin, vasoactin interstinal peptide (VIP), opioids, etc. Contractions of uterine myocytes at the end of pregnancy and during childbirth are stimulated by the hormone oxytocin ; estrogen increases, and progesterone decreases their tone.
Myogenic activity of smooth muscle tissue. The physiological stimulus of smooth myonites is their stretching, which causes depolarization of the sarcolemma and an influx of Ca 2+ ions into the sarcoplasm. Smooth muscle tissue is characterized by spontaneous rhythmic activity (automaticity) due to the cyclically changing activity of calcium pumps in the sarcolemma. Spontaneous activity it is most pronounced in the smooth muscle tissue of the intestine, uterus, and urinary tract; it is much weaker in the muscle tissue of blood vessels. For automation, the most typical cycles are contraction and relaxation with an average period of about 1 minute. (from 0.5 to 2 min). Under normal conditions, this myogenic rhythm of activity is influenced by neural and hormonal signals that strengthen, weaken, coordinate and synchronize the contractile activity of myocytes.
Physiological regeneration of smooth muscle tissue carried out constantly at the subcellular level by updating cellular components.
Smooth muscle hypertrophy serves as its reaction to an increase in functional load, usually associated with its stretching.
NERVOUS TISSUE
Nervous tissue consists of neurons (neurocytes, nerve cells themselves), which have the ability to produce and conduct nerve impulses, and neuroglial cells, which perform a number of auxiliary functions (supportive, trophic, barrier, protective, etc.) and ensure the activity of neurons. Neurons and neuroglia (with the exception of one of its varieties, microglia) are derivatives of the neuronal rudiment.
NEURONS
Neurons (neurocytes, actually nerve cells) - cells of various sizes (which vary from the smallest in the body - in neurons with a body diameter of 4-5 microns - to the largest with a body diameter of about 140 microns). Their total number in the human nervous system exceeds 100 billion (10 11), and according to some estimates reaches one trillion (10 12). By birth, neurons lose the ability to divide, so during postnatal life their number does not increase, but, on the contrary, due to the natural loss of cells, gradually decreases.
