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Muscle Physiology Skeletal muscle o About 40% of body weight is because of skeletal muscles o Voluntary muscles because we can control and initiate contractions o Multinucleated At the time of development, many myoblasts come together with their separate nuclei and fuse to form a single muscle cell. Resulting in multiple nuclei. o Striated Due to regularly arranged myofilaments forming Sarcomeres. Sarcomeres – contractile units Cardiac muscle o Striated Regularly arranged myofilaments Sarcomeres – contractile units o Involuntary o Uninucleated Only one nucleus per cardiac muscle cell o Branched Unique to cardiac muscle o Gap junctions between adjacent muscle cells Shared with smooth muscle but not skeletal Direct communication between cells These gap junctions exist in intercalated disks Smooth muscle o Aka visceral muscles o Line the hollow organs Urinary bladder, uterus, blood vessels, ureter, respiratory passages, ocular, etc. o Spindle-shaped o Uninucleate o There is no regular arrangement of contractile proteins therefore No sarcomeres No striations o So many triggers for smooth muscle to contract Hormones, NT, mechanical stimulation Skeletal muscles respond only to motor neurons stimulation Skeletal muscle Usually attached to bones by tendons o Tendon is a connective tissue which attaches muscle to bone Origin o Closest to the trunk Insertion o More distal Flexor o Brings bones together Extensor o Bones move away Antagonistic muscle groups o Flexor-extensor pairs o Example is biceps and triceps o Biceps cause flexion and triceps cause extension of the forearm
Microanatomy of skeletal muscle o Connective tissue (CT) is pervading and surrounds different muscle structures Forms tendon Gives elasticity to the muscle when once the pulling force is removed o Observe the figure to understand the following terms Epimysium o Is the outermost CT layer outside of the muscle Perimysium o Are the CT surrounding fascicles inside the muscles Endomysium o Is the CT surrounding individual muscle fibers Between muscle fibers o CT eventually tapers off to form tendon that eventually joins to bone o Fascicles Are bundles of muscle cells/fibers Called fibers because the cells are long o Sarcolemma Muscle’s plasma membrane o T-tubules or Transverse tubules Deep invaginations of plasma membrane (sarcolemma) Their function is to conducts action potential deep into the muscle cell o Sarcoplasmic reticulum Endoplasmic reticulum of muscles Extensive network of tubes More extensive than in other cells Stores lots of calcium
Aka dark band Light reflection is not uniform so Anisotropic or A band Have thick filaments and little bit of overlapping thin filaments at the edges o H zone Slightly lighter part of A band in the center In contracting muscle H zone disappears o M line Acts as attachment site for the thick filaments and some more stabilizing proteins like titin o Z disk Is in center of I band Distance between 2 adjacent Z disks is a sarcomere Thin filaments attach to Z o Composition of thick filaments Exclusively made up of myosin Structure of myosin is like golf club Two globular heads Hinge region joins shaft (tail) with heads o Flexible, allows for swiveling movement of head Each myosin molecule has two heavy chains and four light chains Heavy chains extend even into tail, light chains are in head Myosin heads have: ATPase activity, myosin-ATPase ATP binding site Actin binding site Ability to swivel when powered by ATP o Composition of thin filaments Three types of proteins make up the thin filaments, 1. Actin, 2. troponin, 3. tropomyosin Actin o Most abundant protein of thin filaments Tropomyosin – blocks myosin binding sites on actin Troponin- it’s a small protein which can change the shape of tropomyosin. When troponin binds to Ca++ it changes the shape of tropomyosin. When tropomyosin changes its shape, it exposes the myosin binding sites of actin.
Actin Actin is in two forms, G actin and F actin. Globular structures in the above figures are G-actin (G for globular) G actin polymerize into chains – forming into F-actin (for filamentous) o Two chains of F-actin twin around each other Myosin binding site on actin are partially blocked when muscle fiber is not contracting Actin has high affinity for myosin Under normal resting condition the binding sites are partially blocked by tropomyosin o Off-state of tropomyosin blocks the actin partially o Maintained in off-state because of troponin Can change the configuration of tropomyosin from ‘off’ state to ‘on’ state o Titin helps stabilize the thick filament Also helps in bringing the stretched muscle back to its regular resting length Because of its elastic nature o Nebulin helps in the alignment of the thin filament Not elastic Classification of proteins o Contractile proteins Actin and myosin o Regulatory proteins Tropomyosin and troponin o Stabilizing proteins Titin and nebulin Muscle Contraction o Muscle tension Force created by muscle Purpose of muscles is to generate tension o Load Weight that opposes contraction o Contraction Creation of tension in muscle Does not necessarily mean shortening of the muscle all the time o Relaxation Release of tension o To bring about movement, the tension has to be greater than the load o How muscles contract Stimulation of muscle by motor neurons is the first step in muscle contraction Excitation is coupled with contraction
Loose binding Myosin head binds weakly to actin molecule 90-degree angle Detachment of inorganic phosphate (Pi) Initiates power stroke o Pulls the thin filaments towards the center of the thick filament o Pulls actin towards the M line After power stroke, ADP also is detached from the myosin head Then goes to rigor state When muscles are relaxed, they are in loose bound 90 degree state Loosely bound Tropomyosin is blocking binding What is preventing continuous power strokes in living body Lack of calcium Prevents muscles from contracting Need calcium signal for power stroke o Regulatory role of Tropomyosin and troponin When calcium levels increase in cytosol Calcium binds to troponin Troponin-calcium complex pulls Tropomyosin away and exposes myosin - binding sites of actin Myosin binds to actin at these sites and completes power stroke Actin filament moves towards M line As long as there is calcium there can be binding and power stroke Like pulling actin hand over hand o Then, our next question is how are the calcium levels increased to cause these contractions? As action potential reaches axon terminal it causes release of NT (Ach) Always causes excitation (depolarization) Always nicotinic Ach receptor at skeletal muscle o If cardiac muscle the receptor is muscarinic Ach binds with Ach receptor Ion channel receptors Channels open and allow both potassium and sodium to move (2) More sodium will enter than potassium leaving out o Because of concentration gradient o Makes inside of cell positive, outside negative o Transient drastic change = action potential (AP) Action potential spreads (3) on sarcolemma and reaches t- tubules Along t-tubules lie DHP receptors which are functionally linked to another set of receptors called Ryr. Ryr are connected to calcium channels on sarcoplasmic reticulum. When AP enter t-tubules it changes configuration of DHP^1 and that changes Ryr (4) configuration leading to opening of Ca++ channel gates on sarcoplasmic reticulum Calcium released and binds with troponin (5) Allows for power stroke (6) and sliding of thin filament between think filaments When such power strokes happen in many myosin molecules they bring about shortening of sarcomeres and overall contraction of the muscles. You need to understand that myofilaments do not shorten but they slide past each other (like clasping of fingers of both hands, the finger length will not change like myofilaments) causing shortening of sarcomere. (^1) See next page for DHP and Ryr
o Muscle relaxation For muscle to relax you need to reduce the calcium in the cytoplasm Calcium ATPase on the sarcoplasmic reticulum membrane o Brings calcium back into reticulum o Active process that requires energy, ATP For skeletal muscle contraction the source of calcium is from its own sarcoplasmic reticulum Synaptic density o Synaptic vesicles are densely placed in the axon terminal Motor end plate has high density of ion channels especially cationic channels o Monovalent cationic channels, like Na+ and K+ channels On T-tubules you find DHP receptors o Dihydropyridine (DHP) o DHP is mechanically linked to Ryr another sensor which is linked to a channel on sarcoplasmic reticulum. Ryr Ryanodine receptor When not contracting there is a large amount of calcium in the sarcoplasmic reticulum Explanatory pictures
o Do not have a lot in our muscles o Stores energy when muscle is at rest Coupled reaction of CP and ADP o CP + ADP Creatine and ATP Energy source: CP Oxygen use: none Products: 1 ATP, creatine Duration of energy provision: 15 seconds Anaerobic metabolism Glycolysis and lactic acid formation Energy source: glucose Oxygen use: none Products: 2 ATP, lactic acid Duration of energy provision: 30-60 seconds Aerobic metabolism or oxidative phosphorylation Aerobic cellular respiration Energy source: glucose, pyruvic acid, free fatty acids from adipose tissue, amino acids from protein catabolism Oxygen use: required Products: 36 ATP, CO2, H2O Duration of energy provision: hours Muscle Fiber Types (3) Use the table from the PPT slides from Blackboard o Categorized by how they derive energy for contraction (source of energy) and how quickly they can contract Slow-twitch oxidative Fast-twitch oxidative- glycolytic Fast-twitch glycolytic AKA Type I Type II a Type II b Color Dark red (due to lot of myoglobin) Red Pale Speed of development of maximum tension Slowest Intermediate Fastest Myosin ATPase activity Slow Fast Fast Diameter Small Medium Large Contraction duration Longest Short Short Calcium ATPase activity in Sarcoplasmic Reticulum Moderate High High Endurance Fatigue resistant Fatigue resistant Easily fatigued Use Most used: posture Standing, walking Least used: jumping Metabolism Oxidative; aerobic Glycolytic but becomes more oxidative with endurance training Glycolytic; more anaerobic than fast- twitch oxidative- glycolytic Capillary density High Medium Low Mitochondria Numerous Moderate Few Fast-twitch glycolytic has a large diameter because it stores a lot of glycogen Also has a pale color because it does not have many blood vessels Anaerobic muscle is the reason it fatigues easily Slow-twitch oxidative Myoglobin has a great affinity for oxygen like hemoglobin
o Binds oxygen and releases it whenever there is a need o That is why fatigue-resistant Summation of contractions o Single twitch Single Contraction relaxation cycle Muscle relaxes completely between stimuli o Summation Stimuli closer together do not allow muscle to relax fully Cause more tension o Summation leading to unfused tetanus Stimuli are far enough apart to allow muscle to relax slightly between stimuli Unfused tetanus aka staircase phenomenon or treppe or incomplete tetanus Summation is not maximum o Complete tetanus Muscle reaches steady tension High frequency stimulation leads to fused tetanus Longer stronger sustained contractions Motor units o Motor neuron and all of the muscle fibers it innervates o Each unit has its own threshold limit The motor unit with the lowest threshold (most sensitive) will respond first Mechanics of body movement o Isotonic Contractions that create force and move load Muscle will change length Concentric action Shortening of the muscle while movement Lifting dumbbell and pulling it towards your shoulder Eccentric action Lengthening action of the muscle Extending arm while holding dumbbell to place it back on the floor o Isometric Contractions that create force and do NOT move load Like pushing against a wall – no movement Keeping arm perpendicular to the floor while holding a dumbbell and not moving it at all Smooth Muscle Properties o Use less energy than skeletal muscle o Maintain force for long periods o Low oxygen consumption o Very fatigue resistant o Has more actin (8 times more actin than myosin) o Troponin is absent o Calcium source is mostly from outside for contractions o Endoplasmic reticulum very little or absent o Some examples: Urinary bladder and reproductive tract, GI tract aka GI smooth muscles, blood vessels (except capillaries) aka vascular smooth muscles, air passages like bronchi and their divisions aka respiratory smooth muscles, ocular smooth muscles in eye, etc o Why isn’t smooth muscle studied as much as skeletal muscle? It has more variety Anatomy makes functional studies difficult It is controlled by hormones, paracrines, and neurotransmitters So many stimuli to make them contract Can have excitation or inhibition
Troponin is totally absent in smooth muscles o Actin more plentiful Actin is 8x more than myosin in smooth muscle Only 3x more plentiful in skeletal muscle o Has less sarcoplasmic reticulum IP3-receptor channel is the primary calcium channel PIP2 cleaves into two second messengers by phospholipase C o DAG and IP o PIP2 is membrane lipid IP3 leaves the membrane and enters into the cytoplasm and binds with sarcoplasmic reticulum o Primary calcium channel DAG stays in the membrane o External calcium is significant as well as calcium from sarcoplasmic reticulum o Lack sarcomeres Regular pattern is missing Filaments run obliquely Dense bodies are anchoring proteins that act as anchoring site for contractile proteins, like Z discs in skeletal muscles Becomes globular when contracted Myosin heads compared to skeletal muscle Uniformly distributed along the myosin In skeletal muscle they were not in the center part of the thick filament Continuous pulling is possible because of this arrangement Smooth Muscle Contraction o When smooth muscle is stimulated, the calcium channels on the plasma membrane open and allow Ca++ into the cell o Calcium quickly binds with calmodulin (2) o This Ca++-calmodulin complex causes the activation of an enzyme ‘myosin light chain kinase (MLCK)’ (3) Typically through phosphorylation o MLCK in turn phosphorylates light chains of the myosin. This phosphorylation causes myosin to perform the power stroke (4) o As long as the myosin is phosphorylated it will keep performing the power strokes and cause contractions Actin sliding across myosin creating tension (5) Thus myosin plays a lead role in contraction in the smooth muscle. On the contrary, in skeletal the troponin played a lead role in contraction o Explanatory picture
o Control of Smooth Muscle Contraction Membrane receptors on the smooth muscle can be affected by binding to signal ligands or depolarization or stretch Signal ligands would be hormones, NT (norepinephrine, Ach), paracrines Also store-operated calcium channels Constantly keep watch of calcium in the cell If the calcium levels in the cytoplasm are dwindling then will release calcium Smooth Muscle Relaxation o To relax the concentration of calcium should be reduced and phosphate group attached to myosin should be chopped off o Calcium ATPase dumps calcium at the expense of energy (1) Calcium ATPase is on sarcolemma and sarcoplasmic reticulum o Sodium calcium antiporters (1) Transport sodium inside and pump calcium outside Sodium potassium ATPase will then have to pump the sodium outside o Calcium dissociates from calmodulin (2) o Myosin phosphatase enzyme chops phosphates from myosin to make into inactive form (3) o Myosin cannot slide across actin, no power stroke, no tension (4) o Explanatory picture
Smooth Muscle Regulation o Many smooth muscles have dual innervation Controlled by both sympathetic and parasympathetic neurons Aka autonomic nervous system o Hormones and paracrines also control smooth muscle contraction Histamine constricts smooth muscle of airways Paracrine agent, causes contraction Nitric oxide affects regulation of diameter of blood vessels Paracrine agent, causes dilation VERY IMPORTANT MUSCLE SUMMARY CHART Skeletal Smooth Cardiac Appearance under light microscope Striated Smooth Striated Fiber arrangement Sarcomeres Oblique bundles Sarcomeres Fiber proteins Actin, myosin, troponin and tropomyosin Actin, myosin, tropomyosin Actin, myosin, troponin and tropomyosin Control Voluntary; calcium and troponin; fibers independent of one another Involuntary; calcium and calmodulin; fibers electrically linked via gap junctions Involuntary; calcium and troponin; fibers electrically linked via gap junctions Nervous control Somatic motor neuron Autonomic neurons Autonomic neurons Hormonal influence None Multiple hormones Epinephrine Location Attached to bones; a few sphincters close off hollow organelles Forms the walls of hollow organs and tubes; some sphincters Heart muscle Nuclei Multinucleate Uninucleate Uninucleate Fiber structure Large, cylindrical fibers Small spindle shaped fibers Shorter branching fibers T-tubules Yes No Yes Sarcoplasmic reticulum Yes Reduced or absent Yes Contraction speed Fastest Slowest Intermediate Contraction force of single-fiber twitch All or none Graded (depends on amount of calcium; more calcium means more force) Graded (depends on amount of calcium; more calcium means more force) Initiation of contraction Requires input from motor neuron Can be autorhythmic Autorhythmic
