Muscle Physiology PDF

Muscle Physiology Prof.Dr.Mitat KOZ Muscle tissue constitute 50 % of the body weigth. Muscle cells are the main cells in the muscle tissue. Muscle cells are highly specialized cells for the conversion of chemical energy to mechanical energy. Specifically, muscle cells use the energy in ATP to gener...

Muscle Physiology Prof.Dr.Mitat KOZ Muscle tissue constitute 50 % of the body weigth. Muscle cells are the main cells in the muscle tissue. Muscle cells are highly specialized cells for the conversion of chemical energy to mechanical energy. Specifically, muscle cells use the energy in ATP to generate force or do work. Because body’s work can take many forms several types of muscle have evolved. locomotion pumping of blood peristalsis of the foods Muscular System Functions Body movement Maintenance of posture Respiration Production of body heat Communication Constriction of organs and vessels Heart beat In humans, the ability to communicate, whether by speech, writing, or artistic expression, also depends on muscle contractions. The human mind expresses itself by the activity of muscles. Properties of Muscle Contractility Ability of a muscle to shorten with force Excitability Capacity of muscle to respond to a stimulus Extensibility Muscle can be stretched to its normal resting length and beyond to a limited degree Elasticity Ability of muscle to recoil to original resting length after stretched Muscle Tissue Types Skeletal Attached to bones Nuclei multiple and peripherally located Striated, Voluntary and involuntary (reflexes) Cardiac Heart Single nucleus centrally located Striations, involuntary, intercalated disks Smooth Walls of hollow organs, blood vessels, eye, glands, skin Single nucleus centrally located Not striated, involuntary, gap junctions in visceral smooth  Skeletal Muscle (Striated Muscle) Skeletal muscle attaches to the skeleton Microscopically, has stripes called Striations Is voluntary muscle - controlled voluntarily (i.e., by conscious control) Multinucleated Cardiac Muscle Occurs only in the Heart Striated like skeletal muscle but has a Branching pattern with Intercalated Discs It is involuntary-automatic Usually one nucleus, but may have more Neural controls allow the heart to respond to changes by changing the rate of contraction Smooth Muscle Occurs within most organs, arteries and veins, and tube-shaped structures Helps substances move through internal body channels via peristalsis It is not striated It is involuntary It has single nucleus STRUCTURE OF THE MUSCLE CELL A single skeletal muscle cell is known as a muscle fiber. Adult skeletal muscle fibers have diameters between 10 and 100 µm and lengths that may extend up to 25 cm. Embryologic origin: Each muscle fiber is formed during development by the fusion of a number of undifferentiated, mononucleated cells, known as myoblasts, into a single cylindrical, multinucleated cell. differentiation Skeletal muscle differentiation is completed around the time of birth, and these differentiated fibers continue to increase in size during growth from infancy to adult stature, but no new fibers are formed from myoblasts.  If skeletal muscle fibers are damaged after birth as a result of injury, How do they repair ? They cannot be replaced by the division of other existing muscle fibers. However, new fibers can be formed, from undifferentiated cells known as satellite cells. Satellite cells are located adjacent to the muscle fibers and undergo differentiation similar to that followed by embryonic myoblasts. Satellite cells This capacity for forming new skeletal muscle fibers… This capacity for forming new skeletal muscle fibers is considerable but will not restore a severely damaged muscle to full strength. Much of the compensation for a loss of muscle tissue occurs through an increase in the size of the remaining muscle fibers (hypertrophy). Skeletal Muscle: Nerve and Blood Supply In general, each muscle is served by a nerve, an artery, and one or more veins. They enter near the central part of the muscle and branch throughout the muscle Each skeletal muscle fiber (cell) is supplied with a nerve ending that controls contraction Contracting fibers require continuous delivery of oxygen and nutrients via arteries Muscle cells produce metabolic wastes that are removed via veins  Skeletal Muscle – CT Sheaths There are three connective tissue sheaths. These layers of connective tissue make the muscle tissue a resistant and stable structure Endomysium – sheath of delicate CT surrounding each muscle fiber (cell) Perimysium – CT surrounding groups of muscle fibers (fascicles) Epimysium – dense regular CT that surrounds the entire muscle Skeletal Muscle – CT Sheaths At each end of a muscle, the collagen fibers of the endomysium, perimysium, and epimysium come together to form a bundle of fibers called a tendon or a broad tendinous sheet called an aponeurosis. These connective tissues provide the muscle support, strength, flexibility, and also electrical isolation.  Microscopic Anatomy – Skeletal Muscle Fiber/Cell Sarcoplasma = cytoplasma Sorcolemma=cell membrane In addition to the typical organelles, muscle fibers have myofibrils, sarcoplasmic reticulum, and T tubule (modifications of the sarcolemma). Sarcoplasm contains glycosomes (granules of glycogen) and the oxygen-binding protein called myoglobin. Myofibrils - Striations Each muscle fiber is made of many myofibrils that contain the contractile elements of skeletal muscle cells Myofibrils make up about 80% of the muscle volume. Myofibrils are made of myofilaments. Thick and thin filaments Two types of myofilaments made up of contractile proteins – Thick (Myosin) Filaments Thin (Actin) Filaments Ultrastructure of Myofilaments: Thick Filaments Thick filaments are composed of the protein Myosin. The myosin found in the striated muscle is class II myosin. Myosin consists of two head and one tail Ultrastructure of Myofilaments: Thick Filaments Each globular head contains two binding sites, one for actin and one for ATP. The actin binding subunit binds to actin and makes acto-myosin bridges. The ATP binding site also serves as an enzyme—an ATPase that hydrolyzes the bound ATP. The tail regions of the myosin molecule forms thick filament. Thin filament contain regulatory proteins Thin filaments compose of actin, troponin and tropomyosin proteins. Actin is the major component of the thin filament. Two actin strands twist around each other and constitute a long double helix. There are myosin binding sites on actin helix. Tropomyosin molecules are long filaments. Two tropomyosin strands spiral around the actin filament and block the active sites in a relaxed muscle fiber. Troponine molecules attend to thin filaments, binding to tropomyosin and actin. Troponine also binds Ca ions and triggers the contraction. Tropponin has three subunits. One is bound to tropomyosin and is called TnT. The other is bound to actin and called TnI and the third binds Ca and called TnC. Troponin and tropomyosin work together to regulate the attachment of cross bridges to actin, and thus serve as a switch for muscle contraction and relaxation. Structure of Actin and Myosin The arrangement of myofibrils creates a series of repeating dark (anisotropic-A) bands and light (isotropic-I) bands Myofibrils – Striations - Banding  Myofibrils - Striations Dark bands are made up by myosin filaments and showed by letter A. Lihgt bans are mostly made up by actin filaments and showed by letter I. Myosin molecules composed of heavy molecular weight (460.000D) They refract the polarized light 2 times, so it is Anisotropic. Actine molecules have lower molecular weight (40000D). It is more transparent for polarized light and called Isotropic.  Myofibrils - Striations I band has a darker midline called the Z disc or Z membrane(or Z line, (zwischen- between). The distance between two neighboring Z membrane is called sarcomere. A sarcomere is the functional unit of contraction. Sarcomere is the smallest contractile unit of a muscle In contraction, Z membranes are dragged towards the center and the sarcomere shortens.  Myofilaments: Banding Pattern A transverse dark M line is seen in the centre of H band. (helle- Bright) M line represents the connection points of of the myosin tail. Mittel-centre  Other Proteins Titin Nebulin Actinin Dystrophin  Dystrophin Dystrophin is a cytoplasmic protein, It is a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix (connective tissue) through the cell membrane. It is located between the sarcolemma and the outermost layer of myofilaments in the muscle fiber (myofiber).  These proteins are involved in maintaining the elastic structure of the muscle and in transferring the resulting tension to the muscle connective tissue layers during contraction. Various myopathies occur in their deficiency. Transverse Tubules(T tubules) and Sarcoplasmic Reticulum (SR) T tubules are invaginations of muscle cell membrane. It provides rapid transmission of action potential into the muscle cell. SR is a specialization of the endoplasmic reticulum The SR is specially adapted for the uptake, storage, and release of calcium ions, Calcium ions are critical in controlling the processes of contraction and relaxation. Within each sarcomere, the SR consists of two distinct portions. Longitudinal elements Terminal cisternae The longitudinal element forms a system of hollow sheets and tubes that are closely associated with the myofibrils. The ends of the longitudinal elements terminate in a system of terminal cisternae (or lateral sacs). These contain a protein, calsequestrin, that weakly binds calcium, and most of the stored calcium is located in this region. T tubules associate with the paired terminal cisternae to form muscle triads. Skeletal Muscle Contraction For contraction to occur, a skeletal muscle must: 1-Be stimulated by a nerve ending. 2-Propagate an electrical current, or action potential, along its sarcolemma. 3-Have a rise in intracellular Ca2+ levels, the final stimulus for contraction. Electrical Characteristics of Skeletal Muscle Cell Electrical events in skeletal muscle resemble those in nerve cell. However there are some quantitative differences in timing and magnitude. RMP of skeletal muscle is about -90 mV (in nerve -70 mV). The action potential lasts 2-4 ms (in nerve 0,5- 1 ms). The conduction speed of action potantial along the skeletal muscle membrane is ≈ 5 m/s (in axon: it can be 100 m/s). The absolute refractory period in skeletal muscle is 1-3 ms long (in axon: ≈0.5 ms). As in nerves, depolarization is the manifestation of Na influx and repolarization is the manifestation of K efflux. Also as in the nerve cell, the Na-K pumps works during the resting period, and repolarization period of action potantial.  Neuromuscular Junction &Physiology of Motor Units Impulse Transmission From Nerve to Muscle Occurs at the Neuromuscular Junction The contraction of skeletal muscle occurs in response to action potentials that travel down somatic motor neuron axons originating in the CNS. The transfer of the signal from nerve to muscle takes place at the neuromuscular junction, also called the myoneural junction. The Structure of the Neuromuscular Junction On reaching a muscle cell, the axon of a motor neuron typically branches into several terminals, which constitute the presynaptic portion of the neuromuscular junction. Sin Neuromuscular Junction ir-Kas  Sin Neuromuscular Junction ir-Kas Within the axoplasm of the nerve terminals are located numerous membrane-enclosed vesicles containing acetylcholine (ACh). Mitochondria, associated with the extra metabolic requirements of the terminal, are also plentiful.  Sin Neuromuscular Junction ir-Kas The postsynaptic portion of the junction is the muscle cell membrane lying immediately beneath the axon terminals. Here the membrane is formed into postjunctional folds, at the mouths of which are located many nicotinic ACh receptors.  Sin Neuromuscular Junction ir-Kas These are chemically gated ion channels that increase the permeability of the postsynaptic membrane in response to the binding of ACh. Between the nerve and muscle is a narrow space called the synaptic cleft. Acetylcholine must diffuse across this gap to reach the receptors in the postsynaptic membrane. Also located in the synaptic cleft (and associated with the postsynaptic membrane) is the enzyme acetylcholinesterase (AChE). Electrical Events at the Neuromuscular Junction: When the wave of depolarization associated with a nerve action potential spreads into the terminal of a motor axon, several processes are set in motion. The lowered membrane potential causes membrane calcium channels to open and calcium ions enter into the axon. The rise in intracellular calcium causes the cytoplasmic ACh vesicles to migrate to the axon membrane, They fuse with the membrane and release their contents via exocytosis. Electrical Events at the Neuromuscular Junction: When the ACh molecules arrive at the postsynaptic membrane after diffusing across the synaptic cleft, they bind to the ACh receptors. When ACh molecules bind to a receptor, the receptor undergoes a configurational change that allows free passage of sodium and potassium ions. With the opening of the postsynaptic ionic channels, sodium (also calcium) enters the muscle cell and potassium simultaneously leaves. Electrical Events at the Neuromuscular Junction: As a result of the altered permeabilities, a net inward current depolarizes the postsynaptic membrane. This voltage change is called the endplate potential or receptor potential. Electrical Events at the Neuromuscular Junction: Endplate current depolarizes the adjacent membrane and causes voltage-gated sodium channels to open, bringing the membrane to threshold. This leads to an action potential in the muscle membrane. The muscle action potential is propagated along the all muscle cell membrane. Propogation of action potential on muscle mebrane…ir-Kas When the action potential encounters the openings of T tubules, it propagates down the T tubule membrane. This propagation is also resulting in numerous action potentials traveling toward the center of the fiber. The importance of t tubules in the rapid propagation of the action potential on the muscle Note that the T tubules communicate with the outside of the cell membrane, and deep in the muscle fiber, each T tubule lies adjacent to the ends of sarcoplasmic reticulum tubules that surround all sides of the actual myofibrils that contract. Dihydropyridine and Ryanodine Receptors Action potential in T- tubules induces DHP receptors to pull open ryanodine receptor channels, This allows the release of Ca ions from terminal cisternae of sarcoplasmic reticulum. Intracellular Ca levels increase. These events are Muscle contraction called excitation- start. contraction coupling. Neuromuscular Transmission Can Be Altered by Toxins and Drugs. Presynaptic blockade of the neuromuscular junction: Botulinum toxin interferes with ACh release. Bacterium Clostridium botulinum It is a Gram-positive, rod-shaped, anaerobic, spore-forming, motile bacterium with the ability to produce the neurotoxin botulinum. This bacterial toxin is used to treat focal dystonias. Dystonia is a movement disorder in which muscles contract involuntarily, causing repetitive or twisting movements. Focal dystonia is a neurological condition, a type of dystonia, that affects a muscle or group of muscles in a specific part of the body, causing involuntary muscular contractions and abnormal postures. Neuromuscular Transmission Can Be Altered by Toxins and Drugs. Low doses of one type of botulinum toxin ( Botox ) are injected therapeutically to treat a number of conditions, including facial wrinkles, severe sweating, uncontrollable blinking, misalignment of the eyes, and others. Curare-Tubocurarine Postsynaptic blockade: Drugs that partially mimic the action of Ach can be effective blockers. Derivatives of curare, originally used as arrow poison in South America, bind tightly to ACh receptors. This binding does not result in opening of the ion channels, however, and the endplate potential is reduced in proportion to the number of receptors occupied by curare. Muscle paralysis results. Although the muscle can be directly stimulated electrically, nerve stimulation is ineffective. Sliding Filament Model of 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: cross-bridge cycle (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, (4) energizing the crossbridge so that it can again attach to a thin filament and repeat the cycle. Cross-bridge cycling is initiated by calcium entry into the cytoplasm. The cycle begins with the binding of an energized myosin cross-bridge to a thin filament actin molecule (step 1): The binding of energized myosin to actin triggers the release of the strained conformation of the energized bridge, This produces the movement of the bound cross-bridge (sometimes called the power stroke) and the release of Pi and ADP (step 2):  During the cross-bridge movement, myosin is bound very firmly to actin, but This linkage must be broken in order to allow the cross- bridge to be re-energized and repeat the cycle. The binding of a new molecule of ATP to myosin breaks the link between actin and myosin. The binding of ATP at one site on myosin decreases myosin’s affinity for actin bound at another site. Following the dissociation of actin and myosin, the ATP bound to myosin is split (step 4), thereby reforming the energized state of myosin.  Sliding Filament Model of Contraction (abstract) Contraction refers to the activation of myosin’s cross bridges – the sites that generate the force. In the relaxed state, actin and myosin filaments do not fully overlap. With stimulation by the nervous system, myosin heads bind to actin and pull the thin filaments. Actin filaments slide past the myosin filaments so that the actin and myosin filaments overlap to a greater degree (the actin filaments are moved toward the center of the sarcomere, Z lines become closer). Sliding Filament Model of Contraction Relaxed State Fully Contracted Sarcomere Shortening Ca2+ and the Contraction Mechanism At low intracellular Ca2+, tropomyosin blocks the binding sites on actin and myosin cannot attach – this is the relaxed state.  Ca2+ and the Contraction Mechanism As Ca2+ levels rise, ions bind to troponin(TnC) regulatory sites Ca2+ and the Contraction Mechanism Calcium-activated troponin undergoes a conformational change This change moves tropomyosin away from actin’s binding sites Ca2+ and the Contraction Mechanism Displacement of the tropomysosin allows the myosin head to bind and cycle (attach and detach) Contraction begins (sliding of the thin filaments due to action of the myosin cross bridges)