Chapter 09 Lecture Outline* Muscle PDF

Chapter 09 Lecture Outline* Muscle Eric P. Widmaier Boston University Hershel Raff Medical College of Wisconsin Kevin T. Strang University of Wisconsin - Madison *See PowerPoint Image Slides for all fi...

Chapter 09 Lecture Outline* Muscle Eric P. Widmaier Boston University Hershel Raff Medical College of Wisconsin Kevin T. Strang University of Wisconsin - Madison *See PowerPoint Image Slides for all figures and tables pre-inserted into PowerPoint without notes. 1 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.  Muscle Physiology Muscle is classified as: Skeletal muscle Smooth muscle Cardiac muscle Each type of muscle has specific characteristics and functions. 2 Types of Muscle Fig. 9-1 3 Characteristics of a Skeletal Muscle Fiber Skeletal Muscle has some defining characteristics: 1. It is multinucleated 2. It contains many mitochondria 3. It has special structures called Transverse tubules (T tubules) 4. It has myofibrils and sarcomeres 5. It has specific terms for some of the intracellular structures: Sarcolemma = Plasma membrane Sarcoplasm = Cytoplasm Sarcoplasmic reticulum = Smooth ER 4  Myofibrils Myofibrils are the structures that give skeletal and cardiac muscle their characteristic striated appearance. They are orderly arrangements of thick and thin filaments: – Actin (thin) – Myosin (thick) 5 Structure of Skeletal Muscle Fig. 9-2 6 Structure of Sarcomere Fig. 9-3 7  Molecular Mechanisms of Skeletal Muscle Contraction The term contraction does not necessarily mean “shortening.” It simply refers to activation of the force-generating sites within muscle fibers—the cross-bridges. For example, holding a dumbbell at a constant position requires muscle contraction, but not muscle shortening. 8  Sliding Filament Mechanism In this model of contraction 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. The ability of a muscle fiber to generate force and movement depends on the interaction of the contractile proteins actin and myosin. 9 Sliding Filament Mechanism Fig. 9-5 10 Fig. 9-6 11 Thin Filaments and Associated Proteins Actin: Contractile protein Each G actin has a binding site for myosin. Think of pearls strung together on a string and then the strands of pearls are twisted together. Tropomyosin: Regulatory protein Overlaps binding sites on actin for myosin and inhibits interaction when in the relaxed state. 12 Thin Filaments and Associated Proteins Troponin: Regulatory protein Forms a complex with the other proteins of the thin filament (actin and tropomyosin). Troponin binds Ca2+ reversibly and once bound changes conformation to pull tropomyosin away from the myosin interaction sites. Ca2+ binding to troponin regulates skeletal muscle contraction because it moves the tropomyosin away and allows myosin to interact with the actin. 13 Fig. 9-7 14 The Cross-bridge Cycle Fig. 9-8 15 Roles of Troponin, Tropomyosin, and Ca2+ in Contraction Fig. 9-9 16 Action Potentials and Contraction Fig. 9-10 17 Excitation-contraction Coupling Fig. 9-12 18  Sarcoplasmic Reticulum The sarcoplasmic reticulum (SR) in muscle is homologous to the endoplasmic reticulum found in most cells. Ca2+ is stored and is released following membrane excitation. The T-tubules and SR are connected with junctions. These junctions involve two integral membrane proteins, one in the T-tubule membrane, and the other in the membrane of the sarcoplasmic reticulum. The T-tubule protein is a modified voltage-sensitive Ca2+ channel known as the dihydropyridine (DHP) receptor, which acts as a voltage sensor. The protein embedded in the SR membrane is known as the ryanodine receptor, which forms a Ca2+channel. 19  Motor Unit A motor unit is defined as the motor neuron and the skeletal muscle fibers it innervates. One motor neuron innervates many muscle fibers, but one muscle fiber is innervated by only one motor neuron. Within a whole muscle there are many motor units. 20 Motor Units Fig. 9-13 21  The Neuromuscular Junction Stimulation of the nerve fibers to a skeletal muscle is the only mechanism by which action potentials are initiated in skeletal muscle. The nerve cells whose axons innervate skeletal muscle fibers are known as motor neurons (or somatic efferent neurons), and their cell bodies are located in either the brainstem or the spinal cord. The axons of motor neurons are myelinated and are the largest-diameter axons in the body. They propagate action potentials at high velocities, allowing signals from the central nervous system to travel to skeletal muscle fibers with minimal delay. 22  The Neuromuscular Junction The axon terminals of a motor neuron contain vesicles similar to the vesicles found at synaptic junctions between two neurons. The vesicles contain the neurotransmitter acetylcholine (ACh). The region of the muscle fiber plasma membrane that lies directly under the terminal portion of the axon is known as the motor end plate. The junction of an axon terminal with the motor end plate is known as a neuromuscular junction. 23 The Neuromuscular Junction Fig. 9-15 24  The Neuromuscular Junction All neuromuscular junctions are excitatory. In addition to receptors for ACh, the synaptic junction contains the enzyme acetylcholinesterase, which breaks down ACh, just as it does at ACh-mediated synapses in the nervous system. Table 9–2 summarizes the sequence of events that lead from an action potential in a motor neuron to the contraction and relaxation of a skeletal muscle fiber. 25 26 Disruption of Neuromuscular Signaling Curare is a deadly arrowhead poison used by indiginous peoples of South America. It binds strongly to nicotinic ACh receptors. It does not open their ion channels, however, and acetylcholinesterase does not destroy it. When a receptor is occupied by curare, ACh cannot bind to the receptor. Therefore, although the motor nerves still conduct normal action potentials and release ACh, there is no resulting EPP in the motor end plate and no contraction. Because the skeletal muscles responsible for breathing, like all skeletal muscles, depend upon neuromuscular transmission to initiate their contraction, curare poisoning can cause death by asphyxiation. 27 Disruption of Neuromuscular Signaling Neuromuscular transmission can also be blocked by inhibiting acetylcholinesterase. Some organophosphates, which are the main ingredients in certain pesticides and “nerve gases” (the latter developed for chemical warfare), inhibit this enzyme. This results in skeletal muscle paralysis and death from asphyxiation. Nerve gases also cause ACh to build up at muscarinic synapses, where parasympathetic neurons inhibit cardiac pacemaker cells. Thus, the antidote for organophosphate and nerve gas exposure includes both pralidoxime, which reactivates acetlycholinesterase, and the muscarinic receptor antagonist atropine. 28 Disruption of Neuromuscular Signaling Drugs that block neuromuscular transmission are sometimes used in small amounts to prevent muscular contractions during certain types of surgical procedures. One example is succinylcholine, which actually acts as an agonist to the ACh receptors and produces a depolarizing/desensitizing block similar to acetylcholinesterase inhibitors. Nondepolarizing neuromuscular junction blocking drugs that act more like curare and last longer are also used, such as rocuronium and vecuronium. The use of such paralytic agents in surgery reduces the required dose of general anesthetic, allowing patients to recover faster and with fewer complications. Patients must be artificially ventilated, however, to maintain respiration until the drug has been removed from the system. 29 Disruption of Neuromuscular Signaling The toxin produced by the bacterium Clostridium botulinum, blocks the release of acetylcholine from nerve terminals. Botulinum toxin is an enzyme that breaks down proteins of the SNARE complex that are required for the binding and fusion of ACh vesicles with the plasma membrane of the axon terminal. This toxin, which produces the food poisoning called botulism, is one of the most potent poisons known because of the very small amount necessary to produce an effect. Application of botulinum toxin is increasingly being used for clinical and cosmetic procedures, including the inhibition of overactive extraocular muscles, prevention of excessive sweat gland activity, treatment of migraine headaches, and reduction of aging-related skin wrinkles. 30 Mechanics of Single-fiber Contractions A muscle fiber generates force called tension in order to oppose a force called the load, which is exerted on the muscle by an object. The mechanical response of a muscle fiber to a single action potential is known as a twitch. 31 The Phases of a Twitch Contraction There are 3 major phases to a twitch contraction: 1. Latent Period This is the period of time from the action potential to the onset of contraction. The time delay is due to the excitation-contraction coupling. 2. Contraction Phase This is the time that tension is developing due to the cross- bridge cycling. 3. Relaxation Phase This is the time that the tension is decreasing (i.e., relaxing) and is longer than the contraction phase. This is due to the amount of time it takes to get all the Ca2+ sequestered. 32 Twitch Contractions Fig. 9-16 33  Isometric and Isotonic Twitches: Isometric twitches do generate tension but do not shorten the muscle (load is greater than the force generated by the muscle…i.e., postural muscles). Isotonic twitches do shorten the muscle. 34 Load-shortening Relationship Fig. 9-17 35 Load-velocity Relationship Fig. 9-18 36  Frequency-tension Relationship Because a single action potential in a skeletal muscle fiber lasts only 1 to 2 ms but the twitch may last for 100 ms, it is possible for a second action potential to be initiated during the period of mechanical activity. When a stimulus is applied before a fiber has completely relaxed from a twitch, it induces a contractile response with a peak tension greater than that produced in a single twitch (S3 and S4). The increase in muscle tension from successive action potentials occurring during the phase of mechanical activity is known as summation. A maintained contraction in response to repetitive stimulation is known as a tetanus (tetanic contraction). 37 Frequency-tension Relationship Fig. 9-19 Fig. 9-20 38  Length-tension Relationship The spring-like characteristic of the protein titin is responsible for most of the passive elastic properties of relaxed muscle fibers. With increased stretch, the passive tension in a relaxed fiber increases, not from active cross-bridge movements but from elongation of the titin filaments. If the stretched fiber is released, it will return to an equilibrium length, much like what occurs when releasing a stretched rubber band. By a different mechanism, the amount of active tension a muscle fiber develops during contraction can also be altered by changing the length of the fiber. If you stretch a muscle fiber to various lengths and tetanically stimulate it at each length, the magnitude of the active tension will vary with length, as Figure 9– 21 shows. The length at which the fiber develops the greatest isometric active tension is termed the optimal length, L0. 39 Length-tension Relationship Fig. 9-21 40  Skeletal Muscle Energy Metabolism As we have seen, ATP performs three functions directly related to muscle fiber contraction and relaxation. There are three ways a muscle fiber can form ATP: 1. Phosphorylation of ADP by creatine phosphate 2. Oxidative phosphorylation of ADP in the mitochondria 3. Phosphorylation of ADP by the glycolytic pathway in the cytosol 41 Skeletal Muscle Energy Metabolism Fig. 9-22 42  Muscle Fatigue When a skeletal muscle fiber is repeatedly stimulated, the tension the fiber develops eventually decreases even though the stimulation continues. This decline in muscle tension as a result of previous contractile activity is known as muscle fatigue. Additional characteristics of fatigued muscle are a decreased shortening velocity and a slower rate of relaxation. The onset of fatigue and its rate of development depend on the type of skeletal muscle fiber that is active, the intensity and duration of contractile activity, and the degree of an individual’s fitness. 43  Muscle Fatigue Causes Many factors can contribute to the fatigue of skeletal muscle. Fatigue from high-intensity, short-duration exercise is thought to involve at least three different mechanisms: 1. Conduction Failure – The muscle action potential can fail to be conducted into the fiber along the T-tubules, which halts the release of Ca2+ from the sarcoplasmic reticulum. This conduction failure results from the buildup of potassium ions in the small volume of the T-tubule during the repolarization of repetitive action potentials. Elevated external potassium ion concentration leads to a persistent depolarization of the membrane potential, and eventually causes a failure to produce action potentials in the T-tubular membrane. 44  Muscle Fatigue Causes 2. Lactic Acid Buildup – Elevated hydrogen ion concentration alters protein conformation and activity. – Thus, the acidification of muscle by lactic acid may alter a number of muscle proteins, including the proteins involved in Ca2+ release. – The function of the Ca2+-ATPase pumps of the sarcoplasmic reticulum is also affected, which may in part explain the impaired relaxation of fatigued muscle. 45  Muscle Fatigue Causes 3. Inhibition of Cross-Bridge Cycling – The buildup of ADP and Pi within muscle fibers during intense activity may directly inhibit cross-bridge. – Slowing the rate of this step delays cross-bridge detachment from actin, and thus slows the overall rate of cross-bridge cycling. – These changes contribute to the reduced shortening velocity and impaired relaxation observed in muscle fatigue resulting from high-intensity exercise. 46  Muscle Fatigue Causes Central Command Fatigue – Another type of fatigue quite different from muscle fatigue occurs when the appropriate regions of the cerebral cortex fail to send excitatory signals to the motor neurons. – This may cause a person to stop exercising even though the muscles are not fatigued. – An athlete’s performance depends not only on the physical state of the appropriate muscles but also upon the “will to win”— that is, the ability to initiate central commands to muscles during a period of increasingly distressful sensations. 47 Muscle Fatigue Fig. 9-23 48  Types of Skeletal Muscle Fibers Skeletal muscle fibers do not all have the same mechanical and metabolic characteristics. Fibers are classified on the basis of: 1. Their maximal velocities of shortening (fast or slow) 2. The major pathway they use to form ATP—oxidative or glycolytic Fast and slow fibers contain forms of myosin that differ in the maximal rates at which they use ATP. This determines the maximal rate of cross-bridge cycling and thus the maximal shortening velocity. 49  Types of Skeletal Muscle Fibers The second means of classifying skeletal muscle fibers is according to the type of enzymatic machinery available for synthesizing ATP. Some fibers contain numerous mitochondria and thus have a high capacity for oxidative phosphorylation. These fibers are classified as oxidative fibers. Most of the ATP such fibers produce is dependent upon blood flow to deliver oxygen and fuel molecules to the muscle and contain myoglobin. In contrast, glycolytic fibers have few mitochondria but possess a high concentration of glycolytic enzymes and a large store of glycogen. 50  Types of Skeletal Muscle Fibers On the basis of these two characteristics, three principal types of skeletal muscle fibers can be distinguished: 1. Slow-oxidative fibers (Type I) combine low myosin-ATPase activity with high oxidative capacity. 2. Fast-oxidative-glycolytic fibers (Type IIa) combine high myosin-ATPase activity with high oxidative capacity and intermediate glycolytic capacity. 3. Fast-glycolytic fibers (Type IIb) combine high myosin- ATPase activity with high glycolytic capacity. Note that the fourth theoretical possibility—slow- glycolytic fibers—is not found. 51 Types of Skeletal Muscle Fibers Fig. 9-25 52 53 Whole-muscle Contraction Fig. 9-26 54  Control of Muscle Tension The total tension a muscle can develop depends upon two factors: 1. The amount of tension developed by each fiber 2. The number of fibers contracting at any time By controlling these two factors, the nervous system controls whole-muscle tension as well as shortening velocity. 55 Control of Muscle Tension 56  Control of Shortening Velocity Shortening velocity of a whole muscle depends upon the load on the muscle, the types of motor units in the muscle, and the number of motor units recruited to work against the load. 57  Muscle Adaptation to Exercise An increase in the amount of contratile activity increases the size of muscle fibers and increases their capacity for ATP production. “Use it or lose it.” Muscles that are not used will atrophy. There are 2 types of atrophy: – Disuse atrophy (like an arm in a cast) – Denervation atrophy (nerve damage = loss of function) 58 Muscle Movements Fig. 9-27 59 Muscle Movements Fig. 9-28 60 Lever Action of Muscles and Bones Fig. 9-30 61  Skeletal Muscle Disorders A number of conditions and diseases can affect the contraction of skeletal muscle. Many of them are caused by defects in the parts of the nervous system that control contraction of the muscle fibers rather than by defects in the muscle fibers themselves. For example, poliomyelitis is a viral disease that destroys motor neurons, leading to the paralysis of skeletal muscle, and may result in death due to respiratory failure. 62  Muscle Cramps Involuntary tetanic contraction of skeletal muscles produces muscle cramps. During cramping, action potentials fire at abnormally high rates, a much greater rate than occurs during maximal voluntary contraction. The specific cause of this high activity is uncertain, but it is probably related to electrolyte imbalances in the extracellular fluid surrounding both the muscle and nerve fibers. These imbalances may arise from overexercise or persistent dehydration, and they can directly induce action potentials in motor neurons and muscle fibers. Another theory is that chemical imbalances within the muscle stimulate sensory receptors in the muscle, and the motor neurons to the area are activated by reflex when those signals reach the spinal cord. 63  Hypocalcemic Tetany Hypocalcemic tetany is the involuntary tetanic contraction of skeletal muscles that occurs when the extracellular Ca2+ concentration falls to about 40 percent of its normal value. This may seem surprising, because we have seen that Ca2+ is required for excitation-contraction coupling. However, recall that this Ca2+ is sarcoplasmic reticulum Ca2+, not extracellular Ca2+. The effect of changes in extracellular Ca2+ is exerted not on the sarcoplasmic reticulum Ca2+, but directly on the plasma membrane. Low extracellular Ca2+ (hypocalcemia) increases the opening of Na+ channels in excitable membranes, leading to membrane depolarization and the spontaneous firing of action potentials. 64  Muscular Dystrophy This disease is one of the most frequently encountered genetic diseases, affecting an estimated one in every 3,500 males (but many fewer females). Muscular dystrophy is associated with the progressive degeneration of skeletal and cardiac muscle fibers, weakening the muscles and leading ultimately to death from respiratory or cardiac failure. Muscular dystrophies are caused by the absence or defect of one or more proteins that make up the costameres in striated muscle. Costameres (costa = "rib") are clusters of structural and regulatory proteins that link the Z-disks of the outermost myofibrils to the sarcolemma and extracellular matrix. Duchenne muscular dystrophy is a sex-linked recessive disorder caused by a defect in a gene on the X chromosome that codes for the protein, dystrophin. Dystrophin was the first costamere protein discovered to be related to a muscular dystrophy, which is how it earned its name. 65  Myasthenia Gravis It affects about one out of every 7,500 Americans, occurring more often in women than men. The most common cause is the destruction of nicotinic ACh receptor proteins of the motor end plate, mediated by antibodies of a person’s own immune system. A number of approaches are currently used to treat the disease. One is to administer acetylcholinesterase inhibitors (e.g., neostygmine). This can partially compensate for the reduction in available ACh receptors by prolonging the time that acetylcholine is available at the synapse. Other therapies aim at blunting the immune response. Treatment with glucocorticoids is one way that immune function is suppressed. Plasmapheresis is a treatment that involves replacing the liquid fraction of blood (plasma), which contains the offending antibodies. 66  Structure of Smooth Muscle Each smooth muscle cell is spindle-shaped, with a diameter between 2 and 10 µm, and length ranging from 50 to 400 µm. They are much smaller than skeletal muscle fibers, which are 10 to 100 µm wide and can be tens of centimeters long. Smooth muscle cells (SMC) have a single nucleus and have the capacity to divide throughout the life of an individual. SMCs have thick myosin-containing filaments and thin actin- containing filaments, and tropomyosin but NO troponin. The thin filaments are anchored either to the plasma membrane or to cytoplasmic structures known as dense bodies. 67  Structure of Smooth Muscle The thick and thin filaments are not organized into myofibrils, and there are NO sarcomeres, which accounts for the absence of a banding pattern. Smooth muscle contraction occurs by a sliding- filament mechanism. Smooth muscles surround hollow structures and organs that undergo changes in volume with accompanying changes in the lengths of the smooth muscle fibers in their walls. 68 Structure of Smooth Muscle Fig. 9-33 69 Smooth Muscle Contraction and its Control Cross-Bridge Activation: – Cross-bridge cycling in smooth muscle is controlled by a Ca2+regulated enzyme that phosphorylates myosin. Only the phosphorylated form of smooth muscle myosin can bind to actin and undergo cross-bridge cycling. – This is done by myosin light chain kinase (MLCK). – To relax a contracted smooth muscle, myosin must be dephosphorylated because dephosphorylated myosin is unable to bind to actin. This dephosphorylation is mediated by the enzyme myosin light-chain phosphatase (MLCP) 70  Sources of Cytosolic Ca2+ Two sources of Ca2+ contribute to the rise in cytosolic Ca2+ that initiates smooth muscle contraction: 1. The sarcoplasmic reticulum 2. Extracellular Ca2+ entering the cell through plasma- membrane Ca2+ channels. To relax, the Ca2+ has to be removed either to the SR or back to the extra cellular fluid. 71  Membrane Activation Smooth muscle responses can be graded. Input to smooth muscle can be either excitatory or inhibitory. 72 Smooth Muscle Contraction and its Control Fig. 9-34 73 Cross-bridge Activation Fig. 9-35 74  Nerves and Hormones The contractile activity of smooth muscles is influenced by neurotransmitters released by autonomic neuron endings. Unlike skeletal muscle fibers, smooth muscle cells do not have a specialized motor end-plate region. They have swollen regions known as varicosities. Each varicosity contains many vesicles filled with neurotransmitter, some of which are released when an action potential passes the varicosity. Varicosities from a single axon may be located along several muscle cells, and a single muscle cell may be located near varicosities belonging to postganglionic fibers of both sympathetic and parasympathetic neurons. Therefore, a number of smooth muscle cells are influenced by the neurotransmitters released by a single neuron, and a single smooth muscle cell may be influenced by neurotransmitters from more than one neuron. 75  Nerves and Hormones Whereas some neurotransmitters enhance contractile activity, others decrease contractile activity. A given neurotransmitter may produce opposite effects in different smooth muscle tissues. For example, norepinephrine, the neurotransmitter released from most postganglionic sympathetic neurons, enhances contraction of most vascular smooth muscle by acting on alpha-adrenergic receptors, but produces relaxation of airway (bronchiolar) smooth muscle by acting on beta-2 adrenergic receptors. Thus, the type of response (excitatory or inhibitory) depends not on the chemical messenger per se, but on the receptors the chemical messenger binds to in the membrane and on the intracellular signaling mechanisms those receptors activate. 76  Local Factors Local factors, including paracrine signals, acidity, O2 and CO2 levels, osmolarity, and the ion composition of the extracellular fluid, can also alter smooth muscle tension. Responses to local factors provide a means for altering smooth muscle contraction in response to changes in the muscle’s immediate internal environment, independent of long-distance signals from nerves and hormones. Many of these local factors induce smooth muscle relaxation. Nitric oxide (NO) which produces smooth muscle relaxation. NO in a paracrine manner. Some smooth muscles can also respond by contracting when they are stretched. Stretching opens mechanosensitive ion channels, leading to membrane depolarization. The resulting contraction opposes the forces acting to stretch the muscle. 77  Spontaneous Electrical Activity Some types of smooth muscle cells generate action potentials spontaneously in the absence of any neural or hormonal input. The membrane potential change occurring during the spontaneous depolarization to threshold is known as a pacemaker potential. Other smooth muscle pacemaker cells have a slightly different pattern of activity. The membrane potential drifts up and down due to regular variation in ion flux across the membrane. These periodic fluctuations are called slow waves. Pacemaker cells are found throughout the gastrointestinal tract, and thus gut smooth muscle tends to contract rhythmically even in the absence of neural input. Some cardiac muscle fibers and a few neurons in the central nervous system also have pacemaker potentials and can spontaneously generate action potentials in the absence of external stimuli. 78  Souces of Cytosolic Calcium Calcium that initiates smooth muscle contraction comes from both the sarcoplasmic reticulum and from the extracellular fluid entering through plasma-membrane channels. 79 Membrane Activation Fig. 9-37 80 81  Types of Smooth Muscle Single-unit smooth muscles respond to stimuli as a single unit because cells are connected by gap junctions. Multi-unit smooth muscles contain cells that respond to stimuli independently and they contain few gap junctions. 82  Cardiac Muscle Cardiac muscle cells have one to two nuclei that are centrally located. They are striated and use the sliding filament mechanism to contract. They are branching cells with intercalated discs with desmosomes and gap junctions. The gap junctions are critical to the heart’s ability to be electrically coupled. They have large mitochondia that produce the energy needed and prevent the heart from fatiguing. The node cells have the ability to stimulate their own action potentials. This is called automaticity or autorhythmicity. The absolute refractory period is about 250 ms. This prevents tetanic contractions which would interfer with the heart’s ability to pump. 83 Cellular Structure of Cardiac Muscle Fig. 9-39 84 Excitation- Contraction Coupling in Cardiac Muscle Fig. 9-40 85  Skeletal vs Cardiac Muscle Fig. 9-41 86 87