Lecture 4 and 5 Skeletal and smooth muscle physiology PDF

The Neuromuscular Junction The neurons that stimulate skeletal muscle fibers to contract are called somatic motor neurons. Each somatic motor neuron has a threadlike axon that extends from the brain or spinal cord to a group of skeletal muscle fibers. A muscle fiber contracts in response to one or...

The Neuromuscular Junction The neurons that stimulate skeletal muscle fibers to contract are called somatic motor neurons. Each somatic motor neuron has a threadlike axon that extends from the brain or spinal cord to a group of skeletal muscle fibers. A muscle fiber contracts in response to one or more action potentials propagating along its sarcolemma and through its system of T tubules. Muscle action potentials arise at the neuromuscular junction (NMJ) (noo-ro¯-MUS-ku¯-lar), the synapse between a somatic motor neuron and a skeletal muscle fiber A synapse is a region where communication occurs between two neurons, or between a neuron and a target cell—in this case, between a somatic motor neuron and a muscle fiber. At most synapses a small gap, called the synaptic cleft, separates the two cells. Because the cells do not physically touch, the action potential cannot “jump the gap” from one cell to another. Instead, the first cell communicates with the second by releasing a chemical called a neurotransmitter. The Functions of Muscles Collectively, the three types of muscle serve the following functions: · Movement. Muscles enable us to move from place to place and to move individual body parts; they move body contents in the course of breathing, blood circulation, feeding and digestion, defecation, urination, and childbirth; and they serve various roles in communication—speech, writing, facial expressions, and other body language. · Stability. Muscles maintain posture by preventing unwanted movements. Some are called antigravity muscles because, at least part of the time, they resist the pull of gravity and prevent us from falling or slumping over. Many muscles also stabilize the joints by maintaining tension on tendons and bones. · Control of body openings and passages. Muscles encircling the mouth serve not only for speech but also for food intake and retention of food while chewing. Internal muscular rings control the movement of food, bile, blood, and other materials within the body. Muscles encircling the urethra and anus control the elimination of waste. · Heat production. The skeletal muscles produce as much as 85% of one’s body heat, which is vital to the functioning of enzymes and therefore to all metabolism. · Glycemic control. This means the regulation of blood glucose concentration within its normal range. Muscle Filaments Each muscle fiber behaves as a single unit, is multinucleate, and contains myofibrils. The myofibrils are surrounded by sarcoplasmic reticulum and are invaginated by transverse tubules (T tubules). Each myofibril contains interdigitating thick and thin filaments, which are arranged longitudinally and cross-sectionally in sarcomeres. The repeating units of sarcomeres account for the unique banding pattern seen in striated muscle (which includes both skeletal and cardiac muscle). Thick Filaments The thick filaments comprise a large molecular weight protein called myosin, which has six polypeptide chains including one pair of heavy chains and two pairs of light chains Most of the heavy-chain myosin has an α-helical structure, in which the two chains coil around each other to form the “tail” of the myosin molecule. The four light chains and the N terminus of each heavy chain form two globular “heads” on the myosin molecule. These globular heads have an actin-binding site, which is necessary for cross-bridge formation, and a site that binds and hydrolyzes ATP (myosin ATPase). Thin Filaments The thin filaments are composed of three proteins: actin, tropomyosin, and troponin Actin is a globular protein and, in this globular form, is called G-actin. In the thin filaments, G- actin is polymerized into two strands that are twisted into an α-helical structure to form filamentous actin, called F-actin. Actin has myosin-binding sites. When the muscle is at rest, the myosin-binding sites are covered by tropomyosin so that actin and myosin cannot interact Tropomyosin is a filamentous protein that runs along the groove of each twisted actin filament. At rest, its function is to block the myosin-binding sites on actin. If contraction is to occur, tropomyosin must be moved out of the way so that actin and myosin can interact. Troponin is a complex of three globular proteins (troponin T, troponin I, and troponin C) located at regular intervals along the tropomyosin filaments. Troponin T (T for tropomyosin) attaches the troponin complex to tropomyosin. Troponin I (I for inhibition), along with tropomyosin, inhibits the interaction of actin and myosin by covering the myosin-binding site on actin. Troponin C (C for Ca2+) is a Ca2+-binding protein that plays a central role in the initiation of contraction. When the intracellular Ca2+ concentration increases, Ca2+ binds to troponin C, producing a conformational change in the troponin complex. This conformational change moves tropomyosin out of the way, permitting the binding of actin to the myosin heads. Transverse Tubules and the Sarcoplasmic Reticulum The transverse (T) tubules are an extensive network of muscle cell membrane (sarcolemmal membrane) that invaginates deep into the muscle fiber. The T tubules are responsible for carrying depolarization from action potentials at the muscle cell surface to the interior of the fiber. The T tubules make contact with the terminal cisternae of the sarcoplasmic reticulum and contain a voltage-sensitive protein called the dihydropyridine receptor, named for the drug that inhibits it The sarcoplasmic reticulum is an internal tubular structure, which is the site of storage and release of Ca2+ for excitation-contraction coupling. As previously noted, the terminal cisternae of the sarcoplasmic reticulum make contact with the T tubules in a triad arrangement. The sarcoplasmic reticulum contains a Ca2+-release channel called the ryanodine receptor (named for the plant alkaloid that opens this release channel). The significance of the physical relationship between the T tubules (and their dihydropyridine receptor) and the sarcoplasmic reticulum (and its ryanodine receptor) is described in the section on excitation-contraction coupling.  Sliding-Filament Mechanism When force generation produces shortening of a skeletal-muscle fiber, the overlapping thick and thin filaments in each sarcomere move past each other, propelled by movements of the cross bridges. During this shortening of the sarcomeres, there is no change in the lengths of either the thick or thin filaments This is known as the sliding- filament mechanism of muscle contraction. The sequence of events that occurs between the time a cross bridge binds to a thin filament, moves, and then is set to repeat the process is known as a cross-bridge cycle. Each cycle consists of four steps: (1) attachment of the cross bridge to a thin filament, (2) movement of the cross bridge, producing tension in the thin filament, (3) detachment of the cross bridge from the thin filament, and (4) energizing the cross bridge so that it can again attach to a thin filament and repeat the cycle. Each cross bridge undergoes its own cycle of movement independently of the other cross bridges, and at any one instant during contraction only a portion of the cross bridges overlapping a thin filament are attached to the thin filaments and producing tension, while others are in a detached portion of their cycle. Calcium ions provide the most important chemical link in the regulation of muscle protein interactions during the course of excitation-contraction coupling. 1. In resting skeletal muscle, cytoplasmic calcium ion concentration is low, which is about 10−7 M in the region of the myofilaments. Troponin I is attached to myosin binding site on actin and partially covers the myosin binding site. Rest of myosin binding site is covered by tropomyosin filament. 2. Thus, in normal condition, troponin I and tropomyosin inhibits myosin-actin interaction. 3. Troponin T is attached to tropomyosin. 4. Each tropomyosin molecule is held in this blocking position by troponin that is bound to both tropomyosin and actin 5. Thus, the troponin-tropomyosin complex behaves as a relaxing protein that prevents undesirable contraction. The sliding filament model of muscle contraction. a diagram of the sliding filament model of contraction. As the filaments slide, the Z lines are brought closer together and the sarcomeres get shorter. (1) Relaxed muscle; (2) partially contracted muscle; 3) fully contracted muscle. During the cross-bridge cycle, binding of ATP to the myosin head breaks the actin-myosin interaction and brings in relaxation of the muscle. If cellular energy stores are depleted, as happens after death, cross-bridge detachment cannot occur due to lack of ATP. Therefore, the myosin heads remain in the attached state. Following death, the cytoplasmic calcium concentration remains elevated because of the following reasons: 1. Calcium is not pumped back into the sarcoplasmic reticulum in the absence of ATP. 2. Ca2+ diffuses from ECF into the cytoplasm. This is because after death, the muscle membrane becomes inactive, which cannot maintain the high gradient of Ca++ between ECF and ICF, as occurs in life. 3. The inactive membrane of the SR cannot hold back Ca++, which diffuses out of SR to the sarcoplasm. The raised cytoplasmic calcium concentration initiates contraction by exposing the myosin heads on actin and permitting formation of cross-bridges that do not detach due to lack of ATP. This leads to stiffness in the muscle, which is known as rigor mortis. It starts about 3 to 4 h after death and gets completed in about 12 h after death. The stiffness disappears 48 to 60 h after death due to disintegration of muscle proteins. Types of Skeletal Muscle Fibers Although all skeletal muscle fibers are fundamentally alike with respect to the mechanisms of excitation-contraction coupling and force generation, they exhibit significant differences in terms of how quickly they can contract and how they produce most of their ATP. Some muscles (such as the soleus muscle of the leg) contain mostly slow-twitch fibers, which contract relatively slowly. In other muscles (such as the extraocular muscles, which control eye movements), the predominant fibers are fast-twitch fibers, which contract relatively quickly. In still other muscles (such as the gastrocnemius of the leg), the proportion of slow-twitch and fast-twitch fibers is intermediate. As their name implies, slow oxidative fibers contain slow myosin and have a high oxidative capacity, producing most of their ATP by oxidative phosphorylation. Fast glycolytic fibers contain fast myosin and have a high glycolytic capacity, producing most of their ATP through glycolysis. Fast oxidative fibers have a high oxidative capacity and contain fast myosin. (Actually, the myosin ATPase activity in these fibers is intermediate between the slowest and fastest myosin.)  Muscle Metabolism Immediate Energy ATP and creatin phosphate, collectively called the phosphagen system, provide nearly all the energy used for short bursts of intense activity The phosphagen system is especially important in activities requiring brief but maximal effort, such as football, baseball, and weight lifting. Short-Term Energy As the phosphagen system is exhausted, the muscles shift to anaerobic fermentation to “buy time” until cardiopulmonary function can catch up with the muscle’s oxygen demand Long-Term Energy After 40 seconds or so, the respiratory and cardiovascular systems “catch up” and deliver oxygen to the muscles fast enough for aerobic respiration to meet most of the ATP demand The muscle growth that occurs after birth occurs by enlargement of existing muscle fibers, called muscular hypertrophy (hı¯-PER-tro¯ -fe¯; hyper-"above or excessive; trophy“ nourishment), rather than by muscular hyperplasia (hı¯-per-PLA¯ -ze¯-a; - plasis " molding), an increase in the number of fibers. Muscular hypertrophy is due to increased production of myofibrils, mitochondria, sarcoplasmic reticulum, and other organelles. It results from very forceful, repetitive muscular activity, such as strength training. Muscular atrophy (AT-ro¯ -fe¯; a- " without, -trophy " nourishment) is a wasting away of muscles. Individual muscle fibers decrease in size as a result of progressive loss of myofibrils. The muscular dystrophies constitute a group of genetically determined degenerative disorders. Duchenne muscle dystrophy (DMD; described by G.B. Duchenne in 1861) is the most common of the muscular dystrophies.  Myasthenia Gravis Myasthenia gravis is an autoimmune disease characterized by weakness that especially affects the muscles of the eyelids, face, neck, and extremities. Muscle contraction is impaired because the immune system mistakenly produces antibodies that destroy acetylcholine (ACh) receptors. In many cases, the first sign of the disease is a drooping of the eyelids and double vision. Treatment includes drugs that inhibit the enzyme that digests acetylcholine, so that ACh accumulates in neuromuscular junctions. Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig's disease, is a disease that causes the death of neurons controlling voluntary muscles. Some also use the term motor neuron disease for a group of conditions of which ALS is the most common In 1963, Hawking was diagnosed with an early- onset slow-progressing form of motor neurone disease (also known as amyotrophic lateral sclerosis or Lou Gehrig's disease) that gradually paralysed him over the decades.... He died on 14 March 2018 at the age of 76, after living with the disease for more than 50 years  Smooth muscle Smooth muscle is composed of myocytes with a fusiform shape, , and tapering to a point at each end. There is only one nucleus, located near the middle of the cell. Although thick and thin filaments are both present, they are not aligned with each other and produce no visible striations or sarcomeres; this is the reason for the name smooth muscle. Z discs are absent; instead, the thin filaments are attached by way of the cytoskeleton to dense bodies, little masses of protein scattered throughout the sarcoplasm and on the inner face of the sarcolemma. The calcium needed to activate smooth muscle contraction comes mainly from the extracellular fluid (ECF) by way of calcium channels in the sarcolemma. During relaxation, calcium is pumped back out of the cell Unlike skeletal and cardiac muscle, smooth muscle is capable of mitosis and hyperplasia. Thus, an organ such as the pregnant uterus can grow by adding more myocytes, and injured smooth muscle regenerates well  Unitary Smooth Muscle Unitary (single unit) smooth muscle is present in the gastrointestinal tract, bladder, uterus, and ureter. The smooth muscle in these organs contracts in a coordinated fashion because the cells are linked by gap junctions Unitary smooth muscle is also characterized by spontaneous pacemaker activity, or slow waves.  Multiunit Smooth Muscle Multiunit smooth muscles have few if any gap junctions, so the muscle cells function as independent units (see Figure 20.17b). They are innervated by autonomic nerves, and individual cells are under more direct neural control than are cells of single-unit smooth muscles. Multiunit smooth muscles may or may not generate action potentials, and they may be activated hormonally or by local chemical stimuli as well as neurally. They are not stretch-sensitive. Smooth muscles of the hair and feather erectors, eye, large arteries, and respiratory airways are examples of multiunit smooth muscles.  Steps in Excitation-Contraction Coupling in Smooth Muscle The steps involved in excitation-contraction coupling in smooth muscle occur as follows 1-Action potentials occur in the smooth muscle cell membrane. The depolarization of the action potential opens voltage-gated Ca2+ channels in the sarcolemmal membrane. With the Ca2+ channels open, Ca2+ flows into the cell down its electrochemical gradient. This influx of Ca2+ from the ECF causes an increase in intracellular Ca2+ concentration. The action potentials are generally of low amplitude, which is about 60 mV, and the duration is around 100 ms. The depolarization phase is caused by influx of calcium from ECF due to the opening of voltage-gated Ca++ channels. Compared to the striated muscles, the upstroke of actions potential is prolonged in smooth muscles, because the Ca++ channels take more time to open than the Na+ channels. The repolarization phase occurs due to closure of Ca++ channels, which occurs slowly. Opening of voltage-gated K+ channels contributes toward the later part of repolarization. Action potentials are generally observed in visceral smooth muscles. Some smooth muscle cells contract without any change in membrane potential. Junctional Potential Generally, action potentials are not observed in multiunit smooth muscles. Instead, in response to neurotransmitters like Ach, local depolarization called junctional potential is recorded that spreads electrotonically along the muscle fiber and decreases the membrane potential causing calcium influx through the opening of voltage-gated Ca++ channels, leading to contraction. Pacemaker Potential In addition to action potentials, pacemaker potentials are recorded in visceral smooth muscle. However, unlike cardiac muscle, the pacemaker activity is not generated at a fixed location; rather it shifts from place to place. In visceral smooth muscles like intestine, pacemaker activities occur at several sites at the same time and then they travel for a short distance in the muscle.  Steps in Excitation-Contraction Coupling in Smooth Muscle The steps involved in excitation-contraction coupling in smooth muscle occur as follows 1-Action potentials occur in the smooth muscle cell membrane. The depolarization of the action potential opens voltage-gated Ca2+ channels in the sarcolemmal membrane. With the Ca2+ channels open, Ca2+ flows into the cell down its electrochemical gradient. This influx of Ca2+ from the ECF causes an increase in intracellular Ca2+ concentration. 2-Two additional mechanisms may contribute to the increase in intracellular Ca2+ concentration: ligand-gated Ca2+ channels and inositol 1,4,5-triphosphate (IP3)-gated Ca2+ release channels. Ligand-gated Ca2+ channels in the sarcolemmal membrane may be opened by various hormones and neurotransmitters, permitting the entry of additional Ca2+ from the ECF. IP3-gated Ca2+ release channels in the membrane of the sarcoplasmic reticulum may be opened by hormones and neurotransmitters. Either of these mechanisms may augment the rise in intracellular Ca2+ concentration caused by depolarization. 3-The rise in intracellular Ca2+ concentration causes Ca2+ to bind to calmodulin. Like troponin C in skeletal muscle, calmodulin binds four ions of Ca2+ in a cooperative fashion. The Ca2+-calmodulin complex binds to and activates myosin-light-chain kinase. Mechanisms for increasing intracellular [Ca2+] in smooth muscle. 4-When the intracellular Ca2+ concentration decreases, myosin is dephosphorylated by myosin-light-chain phosphatase. In the dephosphorylated state, myosin can still interact with actin, but the attachments are called latch-bridges rather than cross- bridges. The latch-bridges do not detach, or they detach slowly; thus, they maintain a tonic level of tension in the smooth muscle with little consumption of ATP. Relaxation occurs when the sarcoplasmic reticulum reaccumulates Ca2+, via the Ca2+ ATPase, and lowers the intracellular Ca2+ concentration below the level necessary to form Ca2+-calmodulin complexes Excitation-contraction coupling in smooth muscle Growth and proliferation of vascular smooth muscles are stimulated by a variety of growth factors. This is typically seen during pregnancy and in hypertension. In pregnancy: Toward term, estrogen stimulates the hypertrophy (increase in cell size) and hyperplasia (increase in cell number) of myometrium as well as the growth of the connective tissue mass. There is increase in the amount of contractile proteins and the number of gap junctions that helps for an effective and coordinated contraction. Stretch of the uterine wall by the growing fetus also induces expansion of the myometrium. In hypertension: When blood pressure is chronically elevated, the pressure load acts as a stimulus and the walls of the blood vessels undergo hypertrophy and hyperplasia. In addition, if there is sympathetic hyperactivity, increased catecholamines also stimulate the vessel wall proliferation by trophic effect. Angiotensin II stimulates, whereas glucocorticoids inhibit growth of vascular smooth muscles. Some other factors like arachidonic acid derivatives, adenosine, serotonin and heparin like substances also affect smooth muscle hypertrophy.