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Home , Motor unit, Sarcolemma

Muscle Physiology Chapter 11 • Characteristics of • Types of Muscle • • Motor Units • Skeletal • Skeletal Muscle Metabolism • • Characteristics of Muscle • Responsive (excitable) – capable of response to chemical signals, electrical signals, and stretch • Conductive – local electrical change in a cell triggers a wave of excitation that travels along the cell • Contractile – cells shorten when stimulated by converting the chemical energy of ATP into mechanical energy • Extensible – cells are capable of being stretched • Elastic – cells return to original resting length after being stretched • General Characteristics: muscle tissue is composed of , blood vessels, nerves, lymphatics and muscle cells. Types of Muscle • Striated Muscle (cytoplasm has cross striations) – Striated Skeletal Muscle (voluntary muscle) – Striated Cardiac Muscle • Smooth Muscle (cytoplasm without cross striations) Skeletal Muscle • Skeletal Muscle is voluntary striated muscle attached to bones • Voluntary means under conscious control • Cells of skeletal muscle tissue are called muscle fibers = muscle cells = myofibers • Skeletal muscle cells are as long as the whole muscle • Skeletal muscle is a striated muscle. – striated muscle exhibits microscopic alternating light and dark transverse bands or cross striations in the cytoplasm that are from the highly organized contractile proteins of the cytoskeleton Muscle – one of the 600 named units of the human

Fascicle – bundles of muscle fibers that form the visible grain of a muscle

Muscle Fiber – individual skeletal muscle cells

Myofibril – long, thin cords of contractile proteins Multinucleated Skeletal Muscle Fibers Syncytial Skeletal Muscle Development Each muscle fiber has multiple nuclei flattened against the inside of the sarcolemma. Multiple nuclei are from the fusion of multiple myoblasts (derived from a condensation of mesenchymal cells) during development forming a syncytium. A syncytium is a multinucleated mass of cytoplasm surrounded by a single plasma membrane. Satellite Cells outside of the sarcolemma between muscle fibers can multiply to produce a small number of new myofibers or they can add their nuclei to existing muscle fibers.

Skeletal Muscle Fibers • Sarcolemma is the specialized plasma membrane of muscle cells. – sarcolemma is polarized at rest and can be depolarized by acetylcholine released by motor neurons – tubular infoldings of the plasma membrane are called transverse tubules (T-tubules) that penetrate into the cell and carry the electrochemical current into the cell • is the specialized cytoplasm of muscle cells. – sarcoplasm is filled with highly organized myofibrils (bundles of parallel protein of and ) and glycogen for stored energy and myoglobin for storing oxygen • is the specialized of muscle cells. – the sarcoplasmic reticulum is a series of interconnected tubules connected to dilated, storage sacs called that store calcium ions (Ca++) : functional units Muscle Filaments of the

• Sarcomeres are the functional units of muscle • Sarcomeres extend from one Z line to the next Z line. • Thin filaments are actin • Thick filaments are myosin M • Elastic filaments are • Ahm, I Zee! • A band extends from myosin tip to myosin tip. Regions of – A stands for anisotropic which is a term for the way polarized light passes through the the thick filaments giving it a dark appearance. Sarcomere • H band is the central region of the A band and is a region of myosin without actin. – H stands for Helle (German for bright). I A I • M line is a disk of protein that anchors the myosin filaments. Z H Z – M stands for Mittel (German for middle) • I band is the thin filament region – I stands for Isotropic: polarized light passes easily through it giving it a light appearance • Z line is a disc of alpha actinin protein that anchors titin and actin filaments – Z stands for Zwischen (German for M between) Regions of the Sarcomere Electron Micrograph of a Sarcomere

M line Nucleus Contractile Proteins and Regulatory Proteins

• Actin and Myosin are contractile proteins – movements of actin and myosin contract the cell • and are regulatory proteins that act like a switch that starts and stops contraction of muscle cells – The regulatory proteins are dependent upon Ca++ Thick Filaments

• Thick filaments are made of hundreds of myosin molecules • Myosin is arranged in bundles with the heads directed outward in a spiral array around the bundled tails Myosin

• Myosin is composed of two entwined polypeptides (each shaped like a golf club with a spiral handle) • The H Zone of a sarcomere is a region with no heads that contains the M line Thin Filaments • Thin filaments are composed of two strands of fibrous actin composed of 6 or 7 globular actin (G actin) subunits each with an active site. • Tropomyosin molecules cover and block the active sites of 6 or 7 G actin subunits. • One calcium-binding troponin molecule is attached to each tropomyosin molecule Overlap of Thick and Thin Filaments

H band

M line Elastic Filaments • Huge springy protein called Titin is an elastic filament that connects the Z disc to the M line • Titin passes through the bundles of thick filaments • Functions of Titin – keeps thick and thin filaments aligned M with each other – resist overstretching – help the cell recoil to its resting length (provides elasticity) Relaxed versus Contracted Sarcomere • Muscle cells shorten because individual sarcomeres shorten by pulling Z discs closer together. • Notice that filament overlap changes, but neither thick nor thick filaments change length during shortening. • During contraction: – A band length stays the same – H band shrinks – I band shrinks • During relaxation, compressed titin rebounds and pushes Z disks apart to the resting length The Sarcomere in Action

http://www.fbs.leeds.ac.uk/research/contractility/titin.htm The Sarcomere in Action http://www.siumed.edu/~dking2/ssb/muscle.htm#1a Skeletal Muscle Innervation • Skeletal muscles are activated by motor neurons • Motor Neurons branch out of the central nervous system from the skull (cranial nerves) and the spine (spinal nerves) • Somatic motor neurons innervate skeletal muscles • Autonomic motor neurons innervate cardiac muscle, smooth muscle or glands Muscle Innervation

Afferent

Efferent

Efferent Innervation of Skeletal Muscle • Skeletal will not contract unless it is stimulated by a nerve cell – nerve cell = neuron – paralysis is a loss of functional innervation and results in the loss of voluntary control of the muscle and eventually atrophy of the muscle • Axons of motor neurons are branched. – each axon can branch a few times (3-6) or many times (over 200) – Each axon branch contacts one muscle fiber – axons = nerve fibers • A is a and all the muscle fibers it innervates Motor Units • Muscle cells of a Motor Unit are dispersed throughout a muscle – provides ability to sustain long- term contraction as motor units take turns resting • Small Motor Units provide Fine Control – small motor units contain as few as 3-6 muscle fibers per nerve fiber – example: eye muscles • Large Motor Units are for Strength – large motor units have as many as 1000 muscle fibers per nerve fiber – example: gastrocnemius muscle • Neuromuscular Junction (NMJ) is a synapse between a nerve fiber and a muscle cell. • Synapse is the functional connection between a nerve cell and its target cell. • Components of the NMJ – terminal boutton (, synaptic knob, terminal button, axonal swelling, synaptic bulb, end bulb) is the swollen end of a nerve fiber and contains vesicles of the neurotransmitter acetylcholine (ACh) – motor end plate is the specialized region of muscle under the terminal boutton – motor end plate membrane has ACh receptors on junctional folds which bind ACh released from the nerve – acetylcholinesterase (AChE) is an enzyme in the basal lamina in the synaptic cleft that breaks down ACh and causes relaxation – synaptic cleft is the gap between the nerve and muscle cells – Schwann cells cover the axon and the NMJ The Neuromuscular Junction Neuromuscular Junction Animation http://www.mhhe.com/biosci/esp/200 2_general/Esp/folder_structure/su/m4 /s10/sum4s10_7.htm Muscle and Nerve Electrochemical Communication • At rest, muscle cell and nerve cell membranes are polarized (charged). Changes in charge are relayed from one cell to another. • Membrane polarity or charge is measured in units of volts – car battery = 12 volts – flashlight battery = 1.5 volts – muscle cell membrane = .06 volts or 60 millivolts (mV) • Difference in charge across the membrane is called the membrane potential. – Resting Membrane Potential is established by a Na+/K+ exchange pump that results in high [Na+] outside of cell and high [K+] and anions inside of cell resulting in a slightly negative voltage inside the cell (-60 mV). • Sarcolemma depolarizes in response to motor neuron stimulation from release of ACh. • Voltage change spreads across the membrane as an

Action Potential

Opening of Na+ channels is triggered by Resting membrane ACh and allows Na+ to rush in depolarizing potential of -60 mV is the membrane. established by the Na+/K+ Membrane depolarization triggers the ATPase pump and non- opening of voltage activated K+ channels gated K+ channels (K+ leak and closing of Na+ channels. K+ leaves the channels) cell through the open channels. The Na+/K+ pump works to restore the membrane potential back to resting levels. +75

3 4

2 -90

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1 2 3 4 5 Resting Action Action End Plate Hyper- Membrane Potential Potential Potential polarization Potential Depolarization Repolarization Na+ out Na+ out Na+ out Na+ out Na+ out Na+/K+ pump K+ in K+ in K+ in K+ in K+ in non-gated K+ leak K+ out K+ out K+ out K+ out K+ out channels Open ACh Receptor Open as Open as Open as letting Na+ (a ligand-regulated ion Closed long as ACh long as ACh long as ACh in and K+ channel) is present is present is present out Open and voltage-gated Na+ Closed Closed letting Na+ Closed Closed channel in Open and Slowly Slowly voltage-gated K+ channel Closed Closed letting K+ Opening Closing out Na+ pumped Ion primarily responsible out Na+ in Na+ in K+ out K+ out for the membrane voltage K+ leaking K+ out out Animation: Establishing a Resting Membrane Potential http://outreach.mcb.harvard.edu /animations/actionpotential.swf Animations: Sodium-Potassium Exchange Function of the Neuromuscular Junction http://highered.mcgraw- hill.com/sites/0072437316/student_vie w0/chapter6/animations.html# http://highered.mcgraw- hill.com/olcweb/cgi/pluginpop.cgi?it=swf::535:: 535::/sites/dl/free/0072437316/120107/bio_c.swf ::Function of the Neuromuscular Junction Muscle Contraction and Relaxation • Four actions are involved in Muscle Contraction and Muscle Relaxation: – Excitation: action potentials in the nerve lead to formation of action potentials in a muscle fiber – Excitation-Contraction Coupling: action potentials on the sarcolemma activate – Contraction: shortening of a muscle fiber or at least the formation of tension – Relaxation: return of a muscle fiber to its resting length Excitation

• Nerve signal stimulates voltage-gated calcium channels at the synaptic knob resulting in exocytosis of synaptic vesicles containing Ach. • ACh is released into the synaptic cleft. Excitation (continued)

• ACh released from the motor neuron binds to ACh receptors in the sarcolemma. • Binding of ACh to the receptor causes it to open a channel for Na+ and K+. A lot of Na+ rushes in and a little K+ rushes out resulting in a membrane voltage change called the End- Plate Potential. The voltage changes from negative to positive. Excitation (continued)

• The End-Plate Potential (voltage change in the motor end-plate membrane) opens nearby voltage-gated Na+ and K+ channels in sarcolemma producing a depolarization that spreads across the sarcolemma. The spreading depolarization is the Muscle Action Potential. Excitation-Contraction Coupling

• Action potential (membrane depolarization) spreads over the sarcolemma and down into the T tubules. • T tubule membrane depolarization triggers the opening of voltage-gated calcium channels in the sarcoplasmic reticulum allowing release of Ca++ from the sarcoplasmic reticulum into the sarcoplasm. Excitation-Contraction Coupling (cont.)

• Calcium ions (Ca++) released by the SR binds to troponin. • Troponin-tropomyosin complex changes shape and exposes active sites on actin. Contraction

• Myosin ATPase in myosin head hydrolyzes an ATP molecule. • Energy from the ATP “cocks” the myosin head in a high energy extended position. • Myosin head binds to an exposed active site on actin forming a cross-bridge. Contraction (continued) 12. Power Stroke; sliding of thin • Power Stroke: filament over myosin head releases thick filament the ADP and Pi as it flexes pulling the thin filament along. • If ATP is available, ATP binds to the myosin head and it releases the thin filament. • It will attach to a new active site further down the thin filament if Ca++ is still available and bound to troponin. – to prevent slippage, at any given moment, half of the heads are bound to a thin filament, while the other half of the heads are re-setting. Relaxation

• Nerve stimulation ceases and acetylcholinesterase breaks down ACh. • ACh no longer bound to receptors so sarcolemma repolarizes. Acetylcholinesterase degrades ACh into acetate and choline which are reabsorbed and recycled by the presynaptic cell. Enzyme breaks down the ACh within 20 miliseconds. Relaxation (continued)

• Active transport (using ATP) by integral membrane protein pumps in the sarcoplasmic reticulum (SR) removes Ca++ from the sarcoplasm and stores it in the SR where it is bound to the protein calsequestrin. • ATP is needed for muscle relaxation as well as muscle contraction. Relaxation (continued)

• Loss of Ca++ from the sarcoplasm results in troponin- tropomyosin complex moving over the actin active sites which stops formation of cross bridges and prevents muscle tension. • Muscle fiber returns to its resting length due to elastic rebound of titin and the series-elastic components or contraction of antagonistic muscles. Animation: Regulation of Sarcomere Shortening http://www.blackwellpublishing.com/ matthews/myosin.html http://www.wiley.com/college/pratt/047 1393878/student/animations/actin_my osin/actin_myosin.swf go to unit 9 Rigor Mortis • Stiffening of the body beginning 3 to 4 hours after death peaks at 12 hours after death then diminishes over next 48 to 60 hours. • Deteriorating sarcoplasmic reticulum releases calcium. • Calcium activates actin-myosin cross bridging. • ATP is no longer produced after death and without any new ATP, the myosin head remains bound to the actin (does not release). • Actin and Myosin fibers remain bound until myofilaments decay. Neuromuscular Toxins and Paralysis • Many pesticides and “nerve gas” are chemicals that inhibit acetylcholinesterase by binding to it and preventing it from degrading ACh. – minor startle response can cause death through spastic paralysis and suffocation – atropine is an antidote that works by blocking ACh receptors • Tetanus or lockjaw is a spastic paralysis caused by a toxin of the soil bacterium Clostridium tetani. – the toxin blocks glycine, an inhibitor normally produced by the spinal cord that prevents overstimulation of muscles. • Botox - Clostridium botulinum is a related soil bacterium that produces botulinum toxin that blocks ACh release from motor neurons. • Curare causes flaccid paralysis with limp muscles that are unable to contract. – Curare is a South American plant toxin used by indigenous people to make poison darts. – Curare binds to ACh receptors without activating them. – Used as a for surgery, but can cause respiratory arrest. Neuromuscular Toxins and Paralysis • Black Widow Spider Venom causes massive release of ACh that leads to uncontrolled muscle spasms. • Tetrodotoxin (TTX) blocks voltage-gated Na+ channels. – TTX blocks sodium movement into the neuron and the action potential along the nerve membrane ceases. – A single milligram or less of TTX - an amount that can be placed on the head of a pin, is enough to kill an adult. – 10-100 times more toxic than black widow spider venom Myasthenia Gravis • Autoimmune disease where antibodies bind to ACh receptors – Skeletal muscle cells become progressively less sensitive to ACh – Symptoms include: • drooping eyelids and double vision • difficulty swallowing • of the limbs • respiratory failure • Disease affects mostly women between ages of 20 and 40 • Treated with acteylcholinesterase inhibitors, thymus removal or immunosuppressive agents Myasthenia Gravis Symptoms

Drooping eyelids and weakness of muscles of eye movement Length-Tension Relationship

• Amount of tension generated by a muscle depends on the length of the muscle before it is stimulated. • Overly contracted muscle cells develop a weak contraction because the thick filaments are already close to the Z discs and further contraction results in the ends of the thick filaments butting up against the Z disc. • Overly stretched muscle cells also develop a weak contraction because there is too little overlap of thin and thick filaments which does not allow for very many cross bridges too form. • Optimum resting length produces greatest force when muscle contracts. Length-Tension Relationship Muscle Twitch • Threshold is the minimum voltage necessary to produce an action potential in a muscle cell. – a single brief stimulus at threshold voltage produces a quick cycle of contraction and relaxation called a twitch that lasts less than 1/10 second. • A single twitch contraction is not strong enough to do any useful work. Stimulus Frequency and Muscle Tension Twitch Treppe

• Twitch: at low frequency (up to 10 stimuli/sec) each stimulus produces an identical twitch with complete relaxation in between. • Treppe: at moderate frequency (between 10-20 stimuli/sec) the muscle relaxes completely between twitches, but the tension increases with each twitch because calcium is not completely reabsorbed into the SR. Also, the heat produced by muscle contraction increases myosin ATPase efficiency (as in warm-up exercises). Stimulus Frequency and Muscle Tension Incomplete Tetanus Complete Tetanus

• Incomplete Tetanus results from higher frequency stimulation (20-40 stimuli/second) and gradually generates stronger, sustained contractions. – each stimulus arrives before the previous one recovers – this is called temporal summation because it results from the timing of the stimuli. • Complete Tetanus usually results from an artificially high stimulation frequency (40-50 stimuli/second) – muscle has no time to relax between stimulations – twitches fuse into a smooth, prolonged contraction – rarely occurs in the body under natural conditions Asynchronous Contraction

• The reason for the smoothness of muscle contraction during muscle tetany is that the motor units function asynchronously. – throughout an actively contracting muscle, some motor units are contracting as others relax. – the muscle does not lose tension as motor units take turns developing tension within the muscle. Energy for Muscle Contraction: ATP

• ATP is the ONLY source of energy for muscle contraction. • ATP is produced by: – aerobic respiration • produces about 36 ATP per glucose molecule

• requires continuous oxygen supply, produces H2O and CO2 as waste – anaerobic fermentation • produces only 2 ATP per glucose molecule • occurs without oxygen and produces irritating lactic acid as waste Phosphagen Enzyme System Myokinase and Creatine Kinase generate ATP in the absence of O2.

Myokinase uses Pi from ADP.

Creatine Kinase uses Pi from creatine phosphate.

Sources of ATP During Intense Exercise

• Immediate Energy: About a 10 Second supply of ATP from:

– Aerobic metabolism using O2 released from myoglobin in muscle cells.

– Phosphagen System of enzymes that transfers Pi to ADP. • Short-Term Energy: About a 30-40 second supply of ATP from: – Glycogen-Lactic Acid System uses stored glycogen and anaerobic metabolism producing lactic acid. • Long-Term Energy: After about 40 seconds if the respiratory and cardiovascular systems are functioning well, they can catch up to O2 demand for aerobic respiration and supply more than 90% of ATP during sustained exercise. Oxygen Debt • The need to breath heavily after strenuous exercise is to provide maximal oxygen for: – replacing oxygen reserves in myoglobin (red respiratory pigment in muscle) and hemoglobin (red respiratory pigment in red blood cells) – replenishing the phosphagen system – converting lactic acid back into glucose in kidneys and liver – serving the elevated metabolic rate that occurs as long as the body temperature remains elevated from exercise Slow Twitch and Fast Twitch Fibers • Muscles contain a mixture of muscle fiber types based upon their metabolism and morphology • Skeletal Muscle Fiber Types: 1) Slow-twitch fibers (oxidative or red fibers) – abundnat mitochondria, myoglobin and capillaries – use aerobic respiration and are resistant to fatigue – examples: leg and thigh muscles (100msec/twitch) 2) Fast-twitch fibers (glycolytic or white fibers) – sarcoplasmic reticulum releases calcium quickly so contractions are quicker – uses available ATP quickly, then uses enzymes for phosphagen and glycogen-lactic acid systems, but can fatigue quickly – examples extraocular eye muscles (7.5 msec/twitch) 3) Intermediate fibers have combined characteristics of fast and slow twitch and are relatively rare in humans except for endurance- trained athletes. • Proportions of different muscle types in an individual appear to be determined genetically: “a born sprinter” or “ a born marathoner” but small changes in proportions can result from training. Muscle Fiber FG = Fast Glycolytic white fibers SO = Slow Oxidative red fibers Cardiac Muscle • Cardiac muscle cells are short, branched, cells that usually have only one nucleus. • Cardiac muscle cells are linked to each other by intercalated discs. – gap junctions synchronize muscle contractions – desmosomes keep the cells from pulling apart • Cardiac muscle cells are Autorhythmic – initiate their own contraction cycles triggered by pacemaker cells • Cardiac muscle cells use aerobic respiration almost exclusively – very vulnerable to interruptions in oxygen supply – use fatty acids for primary energy storage – large, abundant mitochondria resist fatigue – damaged cells are repaired by fibrosis, not mitosis Cardiac Muscle Smooth Muscle • Fusiform cells with one nucleus – no visible striations or sarcomeres – thin filaments attach to dense bodies scattered throughout sarcoplasm and attached to the sarcolemma – thick filaments are suspended between the thin filaments – gap junctions spread depolarization from cell to cell – calcium for contractions comes from poorly developed SR and from extracellular fluid • If present, nerve supply is autonomic – Neurotransmitter can be either ACh or norepinephrine – Neurotransmitters have different effects in different locations • Contraction and relaxation is very slow in comparison to striated muscle. • Smooth Muscle is very efficient and uses 300 times less ATP to maintain a given tension than skeletal muscle • Smooth muscle can be stimulated by neurotransmitters, hormones, high CO2, low O2, low pH, stretch.

Responses of Smooth Muscle to Stretch

• Stretch opens mechanically-gated calcium channels causing muscle contraction. – example: food in the intestines brings on peristalsis • Stress-relaxation response necessary for hollow organs that gradually fill (urinary bladder). – when stretched gently, tissue briefly contracts then relaxes • Contracts forcefully when greatly stretched. • Contraction force matches degree of stretch. Contraction of Smooth Muscle Cells These cultured rat aorta smooth muscle cell were immunofluorescently labeled with primary anti-vinculin mouse monoclonal antibodies followed by goat anti-mouse Fab fragments conjugated to Cy3 (red fluorescence emission). Note the prominent staining of the cellular attachment network in the central portion and periphery of these cells. In addition, the specimen was simultaneously stained for DNA with the ultraviolet- absorbing probe DAPI, and for the cytoskeletal filamentous actin network with Alexa Fluor 488 conjugated to phalloidin. Images were recorded in grayscale with a QImaging Retiga Fast-EXi camera system coupled to an Olympus BX-51 microscope equipped with bandpass emission fluorescence filter optical blocks provided by Omega Optical. During the processing stage, individual image channels were pseudocolored with RGB values corresponding to each of the fluorophore emission spectral profiles.