Nerve And Muscle Physiology PHG 203 PDF

NERVE AND MUSCLE PHYSIOLOGY DEPARTMENT OF HUMAN PHYSIOLOGY FACULTY OF BASIC MEDICAL SCIENCES REDEEMER’S UNIVERSITY, EDE LECTURER: (DR) MRS DARAMOLA. O. O SESSION: 2022/2023  INTRODUCTION CNS BRAIN...

NERVE AND MUSCLE PHYSIOLOGY DEPARTMENT OF HUMAN PHYSIOLOGY FACULTY OF BASIC MEDICAL SCIENCES REDEEMER’S UNIVERSITY, EDE LECTURER: (DR) MRS DARAMOLA. O. O SESSION: 2022/2023  INTRODUCTION CNS BRAIN SPINAL CORD Figure 1 The functional unit of the central nervous system is the neuron. The neurons transmits electrical signals to one another through their process. There are about 14 billion neurons in the central nervous system. 75% is located in the cerebral cortex. Description of a Neuron: Typically, neurons in the mammalian CNS have the following parts: Cell body; contains nucleus and is the metabolic centre of the neurons Dendrites; extends outwards from soma and arborize extensively Axons; are long fibrous structure that originate from a thickened area of the cell body called axon hillock. Terminal buttons; they arise from the axons. They contain granules in which the synaptic transmitter secreted by the nerves are stored. Myelin sheath; this forms from Schwan and surrounds the axon.  A NEURON Figure 2: Diagram of a motor neuron (Ganong, 2011. 12th edition). Neurons are of different shapes and sizes and are found in different part of the body.  MULTIPOLAR NEURONE Figure 3: multipolar neurons have many poles. One of the poles gives rise to the axon, all others give rise to dendrites. They are found in the brain and spinal cord  BIPOLAR NEURONES Figure 4: Diagram of Bipolar neurons (text book of physiology and anatomy) Bipolar neurons have one axon and one dendrite. Examples include olfactory cells of the nasal cavity, some neurons of the retina and sensory neurons of the inner ear.  UNIPOLAR NEURON ANAXONIC NEURON Figure 5: diagram of unipolar neuron Figure 6: Diagram of anaxonic neuron Unipolar neurons have only a They have multiple dendrite but no single process leading away axon. from the soma. They communicate through their They are represented by the dendrite and do not produce action neurons that carry sensory potentials. signals to the spinal cord. Some are found in the brain and in the retina Cell bodies of neurons tends to be Segregated into compact groups called nuclei or Segregated into compact sheath called laminae that lie within grey matter of CNS or Lie in specialized ganglia that are located within the peripheral nervous system. The nerve fiber of the neurons run in the white matter of the CNS or along the peripheral nerves Groups of nerve fibers running in same direction usually form a compact bundle which can be called nerve tract, peduncle, brachium or pathway.  In the peripheral nervous system, a nerve is made up of many axons bound together in a fibrous envelope called epineurium Fig 7: Nerve fiber types (A and B are myelinated, C is  EXCITATION AND CONDUCTION Nerve have low threshold to stimulus Some nerves are stimulated by electric stimulus while others by chemical stimulus Upon stimulation, there are two types of responses that can be produced in a nerve namely; Local potential (nonpropagated) Action potential (propagated) Nerve response is made possible by the conduction of ions across the cell membrane  In neurons, the resting membrane potential is usually about –70 mV. A membrane potential results from separation of positive and negative charges across the cell membrane. In order for a potential difference to be present across a membrane lipid bilayer, two conditions must be met. First, There must be an unequal distribution of ions of one or more species across the membrane (i.e, a concentration gradient). The membrane must be permeable to one or more of these ion species.  Types of muscle fiber Muscle fiber is of three types namely; skeletal, cardiac, smooth Cardiac muscle: has cross-striations It is functionally syncytial and can be modulated via the autonomic nervous system It has its own pace makers that discharge spontaneously and make the muscle contract rhythmically without external innervation. Smooth muscle: lacks cross-striations and can be further subdivided into two broad types: unitary (or visceral) smooth muscle and multiunit smooth muscle. The type found in most hollow viscera is functionally syncytial and contains pacemakers that discharge irregularly. The multiunit type found in the eye and in some other locations is not spontaneously active and resembles skeletal muscle in graded contractile ability.  Skeletal muscle A skeletal muscle is an organ that consists of various integrated tissues namely; skeletal muscle fibers (several fibers are organized into bundles called fassicles and each fiber is made up of several myofibrils), blood vessels, nerve fibers, and connective tissue. Each skeletal muscle has three layers of connective tissue that enclose it namely; Epimysium: it is dense and irregular and allows muscles to contract powerfully while maintaining its structural integrity and giving it its independence. Perimysium: it is a midlle layer connective tissue that surrounds the fassicles Endomysium: it surrounds the muscle fibre, it plays a role in transferring force produced by the muscle fibers to the tendons 12  Skeletal muscle Figure 8: structural arrangement of skeletal muscle 13  Skeletal muscle In skeletal muscles that work with tendons to pull on bones, the collagen in the three connective tissue layers intertwines with the collagen of a tendon. At the other end of the tendon, it fuses with the periosteum coating the bone. The tension created by contraction of the muscle fibers is then transferred through the connective tissue layers, to the tendon, and then to the periosteum to pull on the bone for movement of the skeleton. Skeletal muscle cells are called myofibers. They are long and cylindrical Each myofiber has many nuclei which allows for production of the large amounts of proteins and enzymes needed for maintaining normal function of the cell. 14  Skeletal muscle It also contain cellular organelles present in other cells in specialized form. Of particular interest is its specialized smooth endoplasmic reticulum called sarcoplasmic reticulum (SR). It stores, releases, and retrieves calcium ions (Ca ++). The plasma membrane of muscle fibers is called the sarcolemma. the cytoplasm is referred to as sarcoplasm. Within a muscle fiber, proteins are organized into structures called myofibrils that run the length of the cell and contain sarcomeres connected in series. 15  Skeletal muscle The sarcomere is the smallest functional unit of a skeletal muscle fiber and is a highly organized arrangement of contractile, regulatory, and structural proteins. It is the shortening of these individual sarcomeres that lead to the contraction of individual skeletal muscle fibers (and ultimately the whole muscle). 16  Skeletal muscle Fig. 9: structure of myofibril myofibril 17 Molecular structure of thick and thin filament A sarcomere is defined as the region of a myofibril contained between two cytoskeletal structures called Z-discs (also called Z-lines). The striated appearance of skeletal muscle fibers is due to the arrangement of the thick and thin myofilaments within each sarcomere. The dark striated A band is composed of the thick filaments containing myosin, which span the center of the sarcomere extending toward the Z-dics. The thick filaments are anchored at the middle of the sarcomere (the M-line) by a protein called myomesin. 18 Molecular structure of thick and thin filament The lighter I band regions contain thin actin filaments anchored at the Z-discs by a protein called α-actinin. The thin filaments extend into the A band toward the M-line and overlap with regions of the thick filament. The A band is dark because of the thicker mysoin filaments as well as overlap with the actin filaments. The H zone in the middle of the A band is a little lighter in color, because the thin filaments do not extend into this region. Because a sarcomere is defined by Z-discs, a single sarcomere contains one dark A band with half of the lighter I band on each end. 19 Molecular structure of thick and thin filament During contraction the myofilaments themselves do not change length, but actually slide across each other so the distance between the Z-discs shortens. The length of the A band does not change, but the H zone and I band regions shrink. These regions represent areas where the filaments do not overlap, and as filament overlap increases during contraction these regions of no overlap decrease. The thin filaments are composed of two filamentous actin chains (F-actin) comprised of individual actin proteins. Within the filament, each globular actin monomer (G-actin) contains a mysoin binding site and is also associated with the regulatory proteins, troponin and tropomyosin. 20 Molecular organizations of proteins in thick and thin filaments The troponin protein complex consists of three polypeptides. Troponin I (TnI) binds to actin, troponin T (TnT) binds to tropomyosin, and troponin C (TnC) binds to calcium ions. Troponin and tropomyosin run along the actin filaments and control when the actin binding sites will be exposed for binding to myosin. Thick myofilaments are composed of myosin protein complexes, which are composed of six proteins: two myosin heavy chains and four light chain molecules. The heavy chains consist of a tail region, flexible hinge region, and globular head which contains an Actin-binding site and a binding site for the high energy molecule ATP. 21  Molecular structure of thick and thin filament The heavy chain is the most important factor for generating force The light chains play a regulatory role at the hinge region. Hundreds of myosin proteins are arranged into each thick filament with tails toward the M-line and heads extending toward the Z-discs. Titin, which is the largest known protein and springy in nature, helps align the thick filament with the thin one so that the contractile machinery of the sarcomere will work. Titin is anchored at the M-Line, runs the length of myosin, and extends to the Z disc. The thin filaments also have a stabilizing protein, called nebulin, which spans the length of the thick filaments. 22 Molecular structure of thick and thin fillament Fig. 10: structure of sarcomere 23  The sliding filament model of contraction The arrangement and interactions between thin and thick filaments allows for the shortening of the sarcomeres which generates force. When signaled by a motor neuron, a skeletal muscle fiber contracts as the thin filaments are pulled and slide past the thick filaments within the fiber’s sarcomeres. It is important to note that while the sarcomere shortens, the individual proteins and filaments do not change length but simply slide next to each other. This process is known as the sliding filament model of muscle contraction 24 The sliding filament model of contraction Fig. 11 25 The sliding filament model of contraction The filament sliding process of contraction can only occur when myosin-binding sites on the actin filaments are exposed by a series of steps that begins with Ca + + entry into the sarcoplasm. Tropomyosin winds around the chains of the actin filament and covers the myosin- binding sites to prevent actin from binding to myosin. The troponin-tropomyosin complex uses calcium ion binding to TnC to regulate when the myosin heads form cross-bridges to the actin filaments. Cross-bridge formation and filament sliding will occur when calcium is present, and the signaling process leading to calcium release and muscle contraction is known as Excitation-Contraction Coupling. 26  NEUROMUSCULAR TRANSMISSION Neuromuscular junction The terminal buttons of axons that innervates skeletal muscles fits into junctional folds which are depressions in the motor end plate. The space between the nerve and the motor end plate is comparable to the synaptic cleft at synapses. The whole structure is known as the neuromuscular, or myoneural junction. Fig 12: Pictoral diagram of a neuromuscular junction.  SEQUENCE OF EVENTS DURING TRANSMISSION Impulse arrives at the terminal buttons and cause an increase in its permeability to Ca+ Upon influx of Ca+, it triggers the exocytosis of acetylcholine containing vesicles. ACH diffuses to the muscle type acetylcholine nicotinic receptor.  SEQUENCE OF EVENTS DURING TRANSMISSION The above results in increase membrane conductance of Na+ and K+. Influx of Na+ produces depolarizing potential (end plate potential). The current sink created then depolarizes the adjacent muscle membrane to its firing level. The muscle action potential, in turn, initiates muscle contraction. ACH is thereafter removed from the NMJ by acetyl cholinesterase attached mainly to the spongy layer of fine connective tissue that fills the synaptic space Fig 13: Pictoral representation of events at neuromuscular junction. Molecular Mechanism of Muscle Contraction The combination of ca++ with Troponin C tugs on tropomysin molecule and moves it deeper into the groove between 2 actin strands. The heads of myosin bridge gets attracted to the active site of actin filament leading to changes in intramolecular forces between the head and arm of the cross-bridge, forcing the head to tilt toward the arm to drag the actin filament along with it. This is called power stroke. After tilt, the head breaks away from the active site and returns to its normal perpendicular direction and combines with a new active site father down along the actin filament and another power stroke occurs. This continues until actin is pulled towards the center of myosin and it is called the walk along theory of contraction. 32  Excitation contraction coupling Transverse Tubule Sarcoplasmic Reticulum System  Excitation contraction coupling Structure of sarcotubular system The sarcoplasm of muscle cells possess a specially developed system of tubules known as sarcotubular system. It helps in transmission of impulse all over the muscle cells. The sarcotubular system consists of two kinds of tubules— transverse tubules and longitudinal tubules. Transverse tubules- The sarcolemma forms regular invaginations which insert between myofibrils, termed transverse tubules (T-tubules). The role of t-tubule is to maintain the SR calcium store under the tight control of membrane depolarization via the voltage gated calcium channel DHPR (Dihydhropyridine Receptor), located on T-tubule membranes. 34  Excitation contraction coupling Structure of sarcotubular system Longitudinal tubules The smooth endoplasmic reticulum of muscle cells are specially developed and modified into some tubules that remain arranged longitudinally between the adjacent transverse tubules. These are called longitudinal tubules or L-tubules. The L-tubules arborize to form a reticulum (or network) at the center of the sarcomere, hence they are collectively called sarcoplasmic reticulum (SR). The peripheral ends of the L-tubules expand to form terminal cisternae that remain in contact with the transverse- tubules. The close association of one T-tubule with two terminal cisternae on both sides of the tubule forms the triad 35 Structure of sarcotubular system Fig. 14: Diagram illustrating structure of sarcotubular system. 36  Excitation contraction coupling Release of Calcium Ions by the Sarcoplasmic Reticulum The SR contains high concentration of calcium ions. Upon action potential on the T-tubule membrane which also transfers current to the SR membrane, large amount of Ca2+ is released in to the sarcoplasm. Ca2+ diffuse to the adjacent myofibrils where it bind strongly with TnC to elicit muscle contraction that continues as long as Ca2+ is present in the sarcoplasm. The SR has continually active Ca2+ pump in its walls to help sequester Ca2+ away from the myofibrils and back into the sarcoplasmic tubules. Also, present in the SR is calsequestrin, a protein that can bind more calcium.  Excitation contraction coupling Fig. 15: Release of Calcium Ions by the Sarcoplasmic Reticulum  Smooth muscle contraction Smooth muscle Length: 20 -500 µm Diameter: 1 - 5 µm Also bears the actin and myosin fillaments. Types 1. multi-unit smooth muscle 2. Unitary smooth muscle  SMOOTH MUSCLE PHYSIOLOGY There are two types of smooth muscles namely: Multi-unit smooth muscle Unitary smooth muscle Multi-unit smooth muscle: Each fiber is discrete and operates independently. Is is often innervated by a single nerve ending. The outer surface is covered by a thin layer of basement membrane-like substance which helps to insulate the separate fibers from one another Each fiber can contract independently from others. Their control is mainly exerted by nerve signals. They seldom exhibits spontaneous contraction. Examples are cilliary muscles of the eye, the iris and piloerector muscle 40  SMOOTH MUSCLE PHYSIOLOGY Unitary smooth muscle: The fibers in this type of muscle are usually aggregated into sheets or bundles and their cell membrane are adherent to one another at multiple points. The cell membranes are joined by many gap junctions. This type of organization causes the muscle fiber to contract as a single unit. They are usually known as syncitial smooth muscle. They are found in the walls of viscera and are so-called visceral smooth muscle. Examples are muscles of the gut, bile ducts, ureters, uterus and many blood vessels 41  SMOOTH MUSCLE PHYSIOLOGY Fig. 16: Diagrams showing multi-unit smooth muscle (A) and unitary smooth muscle (B) 42  Chemical basis for smooth muscle contraction Smooth muscles contains both actin and myosin filaments but the actin filament is devoid of troponin complex and they do not have striated arrangements. The contractile processes is activated by calcium and ATP. Actin filaments are attached to dense bodies, some of which are attached to the cell membrane while others are dispersed in the cell. Some of the dense bodies of adjacent cells are also bond together by intercelluar proteins and bridges. This enables force of contraction to be transmitted from one cell to the next. Interspersed among the many actin are a few myosin filaments. 43  Chemical basis for smooth muscle contraction Fig. 17: Structure of smooth muscle. The upper left hand fiber shows actin filament radiating from dense bodies. The lower left han fibre and the right hand diagram show the relation of myosin filament. to actin filament. 44  Regulation of contraction by calcium Smooth muscles contain large amount of regulatory proteins called calmodulin in the myofibrilar fluid. When an action potential causes the release of calcium from the sarcoplasmic reticulum (SR), it binds with calmodulin, this combination joins with and activates myosin kinase, a phophorylating enzyme. One of the light chain of the phosphorylating head becomes phosphorylated in response to the myosin kinase so that the head of the crossbridges binds with actin filament and proceed through the entire cycling process as in skeletal muscle. Cessation of contraction is achieved by the role of an enzyme namely myosin phosphatase located in the fluid of the smooth muscle cell. It splits the phosphate from the regulatory chain, then the cycling stops and contraction ceases. 45  PATHOPHYSIOLOGY Muscle Hypertrophy When the total mass of a muscle increases, this is called muscle hypertrophy. Muscle hypertrophy results from increase in the number of actin and myosin filaments in each muscle fiber. Hypertrophy occurs to a much greater extent when the muscle is loaded during the contractile process. Only a few strong contractions each day are required to cause significant hypertrophy within 6 to 10 weeks. The rate of synthesis of muscle contractile proteins in the myofibril is far greater when hypertrophy is developing.  PATHOPHYSIOLOGY Muscle Hypertrophy (cont’d) some of the myofibrils also do split within hypertrophying muscle to form new myofibrils. As myofibrils increase in size, the enzyme systems that provide energy also increase, e.g., the enzymes for glycolysis. Another type of hypertrophy occurs when muscles are stretched to greater than normal length, causing new sarcomeres to be added at the ends of the muscle fibers. Several new sarcomeres can be added per minute in newly developing muscle.  PATHOPHYSIOLOGY Muscle Atrophy The process of decreases in total mass of muscle is called muscle atrophy. When a muscle remains unused for many weeks, the rate of decay of the contractile proteins is more rapid than the rate of replacement. Therefore, muscle atrophy occurs. When a muscle continually remains shortened to less than its normal length, sarcomeres at the ends of the muscle fibers can actually disappear. Loss of muscle nerve supply that produce contractile signal, thereby, maintaining muscle size is a major cause of atrophy.  PATHOPHYSIOLOGY Muscle Atrophy (cont’d) Shortly, degenerative changes begin to appear in the muscle fibers. The nerve supply to the muscle may grow back rapidly and full return of function occur in 3 months, if not, the capability of functional return becomes reduced and no function can be returned after 1 to 2 years. In the final stage of denervation atrophy, most of the muscle fibers are destroyed and replaced by fibrous and fatty tissue. The fibers that do remain are composed of a long cell membrane with a lineup of muscle cell nuclei but with few or no contractile properties  PATHOPHYSIOLOGY Muscle Atrophy (cont’d) The fibrous tissue that replaces the muscle fibers also continues shortening for many months, which is called contracture. contracture is debilitating and disfiguring but can be avoided by daily stretching of the muscles.  PATHOPHYSIOLOGY Hyperplasia of Muscle Fibers Hyperplasia is the moderate increase in number of muscle fibers owing to conditions of extreme muscle force generation. The mechanism is linear splitting of previously enlarged fibers.  PATHOPHYSIOLOGY Myasthenia Gravis It is the inability of neuromuscular junctions to transmit enough signals from nerve fibers to muscle fibers, thereby leading to muscle paralysis. It is an autoimmune disease in which patients developed immunity against their own acetylcholine-activated ion channels The end plate potentials that occur in the muscle fibers becomes too weak to stimulate the muscle fibers High intensity of the disease causes the patient to die of paralysis. It can be ameliorated for several hours by administering anticholinesterase drug.  PATHOPHYSIOLOGY Muscle Fatigue Prolonged and strong contraction of a muscle leads to muscle fatigue. Muscle fatigue increases in almost direct proportion to the rate of depletion of muscle glycogen. Therefore, fatigue results mainly from inability of contractile and metabolic processes of the muscle fibers to continue supplying the same work output. Also, transmission of the nerve signal through the neuromuscular junction can diminish at least a small amount after intense prolonged muscle activity, thus further diminishing muscle contraction. Interruption of blood flow through a contracting muscle leads to almost complete muscle fatigue within 1 or 2 minutes because of the loss of oxygen and nutrient supply.  PATHOPHYSIOLOGY Rigor Mortis Several hours after death, all the muscles of the body contract and become rigid, even without action potentials, this is called “rigor mortis. This results from loss of all the ATP, which is required to cause separation of the crossbridges from the actin filaments during the relaxation process. The muscles remain in rigor until the muscle proteins deteriorate about 15 to 25 hours later, which presumably results from autolysis caused by enzymes released from lysosomes.