Muscle GSBS week1pt2 PDF

Skeletal and Smooth Muscle https://app.sli.do/event/1hMPPMdTtPZMYDz8qGS4qT  ⑭ Muscle Almost all cells have intracellular machinery for movement The contraction specialists of...

Skeletal and Smooth Muscle https://app.sli.do/event/1hMPPMdTtPZMYDz8qGS4qT  ⑭ Muscle Almost all cells have intracellular machinery for movement The contraction specialists of the body, however, are the muscle cells (filament dense ①Skeletal ②Cardiac ③ Smooth Muscle Cells Low power light microscope of skeletal muscle fibers Highly developed ability to contract, develop tension and do work  Contraction of muscle allows: 1. Purposeful movement of the body Skeletal in relation to the environment 2. Manipulation of external objects 3. Propulsion of contents through (cardiac hollow organs 4. Empty the contents of organs (smooth) to the environment Muscle comprises the largest group of tissues in the body ~ ½ of body weight Skeletal muscle: 660 in the adult human – 40% body weight in men – 32% in women Smooth and heart = 10%  Classification: Functional vs Structural structure-bonding pattern same filaments Not As Organized (Somotie( (Autonomic) Organization of the Nervous System Effector organs carry out the orders  Levels of organization in a skeletal muscle Fiber Whole muscle = an organ Muscle fiber = a cell - relatively large (up to 2.5 ft) repeating subunits - multinucleated (to maintain = Sacromere high protein production Fascicles of such a large cell) Organelle Myofibril = intracellular structure Thick and thin filaments = myofilaments Myosin , Activ Functional unit [ Myosin and actin = contractile proteins Myofilaments  Contractile Proteins Thick filaments: several hundred myosin (heads and tails) when connects to Actin Light chains enhance myosin-actin interactions  Thin filaments: mostly actin (helix) to porm polymence filaments 3 subunits cat binds to move out of Saysovermys bind a way Regulatory proteins  Changes in banding pattern during shortening Light microscope: light and dark bands Changes in banding pattern during shortening A (dark): thick and thin that overlap; thick - filaments are found only in the A band Changes in banding pattern during shortening I band: Remaining portion of thin filaments that do not project into A Changes in banding pattern during shortening Z line: in the middle of the I band; sarcomere is Z line to Z line protein , I line to t line  Changes in banding pattern during shortening H zone: lighter area in middle of A band, where thin filaments do not reach Shortensoverlap  Changes in banding pattern during shortening M line: mid point of the sarcomere  Medical Mnemonic Muscle sarcomere: – Only one vowel in "dark" and "light" DArk band is the A band LIght band is the I band d Muscle sarcomere bands: – "Zee Intelligent Animal Has Muscle": From the Z line working inward: Z I A H M  Which of the following is the light band of the sarcomere? A. A band B. H zone C. I band D. Z line  Which of the following remains the same width during contraction? A. A band - B. H zone C. I band  Which of the following describes a sarcomere? A. 1 whole A band and ½ of each I band located on either side B. 1 Z line to the next Z line C. The functional unit of skeletal muscle OD. All of the above  Molecular Basis of Muscle Contraction Excitation-Contraction Coupling – Resting State Ca2+ is absent in sarcoplasm; SERCA actively pump Ca2+ into SR Regulatory proteins troponin & tropomyosin cover actin’s binding site No attachment is possible between actin & myosin filaments; muscle cell is relaxed  Excitation-Contraction Coupling – Excitation of Muscle Cell Ca2+ influx gets destroyed depolarizatenope a e ol Nicotinic cholinergic Cation channels open, Na+ moves in  an EPP; similar to an EPSP but EPP is larger  Excitation-Contraction Coupling – The Result of Excitation Specialized membranes that take AP from surface to center of cell i SR = modified ER, consists of interconnecting tubules T-Tubule runs perpendicular surrounding each myofibril like a mesh sleeve to surface Spread of AP down T-tubules Direct physical interaction b/w 2 receptors activates Dihydropyridine receptors (DHPR) * sn't Allow Truncated dry in , but stuppert be moves way I DHPR, normally a voltage-gated Ca2+ channel, functions in skeletal muscle as a voltage sensor, triggering intracellular Ca2+ release via RyR Ryanodine receptor (RyR) Shift of DHPR- > RyR to mover Both DHPR and RyR are Ca2+ channels  Excitation-Contraction Coupling – Steric Block Model Troponin sterie canis blondelt - Muhibito -bind - Ca2+ binds to troponin O - Troponin changes its shape - Troponin-tropomyosin complex is physically pulled aside - Actin’s binding sites uncovered  Excitation-Contraction Coupling – Cross-bridge Cycling Before X-bridge ever links: - ATP hydrolyzed by myosin ATPase - ADP and P remain attached to myosin - Energy stored in X-bridge (“cocked” and ready to be fired)  Excitation-Contraction Coupling – Cross-bridge Cycling Ca2+ removes inhibitory influence  Excitation-Contraction Coupling – Cross-bridge Cycling - Energized myosin X-bridge binds - Contact “pulls the trigger” Power stroke - ADP and P released  Excitation-Contraction Coupling – Cross-bridge Cycling opening up o site 4 Q new ATP Binding of fresh J dont Combine ATP breaks linkage 2 gether between actin and myosin ( affinity for actin) ATP hydrolyzed  Conformational change of head   Ca2+  ATP Which is responsible for removing the steric inhibition for the act of contraction? Ga Which is responsible for detachment? ATP  Excitation-Contraction Coupling – Return to Resting State 1. Neural excitation stops 3. Muscle excitation stops 2. Previously released ACh is broken down by AChase 5. SERCA pumps Ca2+ back 4. Dihydropyridine channels close; diffusion of Ca2+ out of SR stops 6. Actin’s binding sites are covered; actin slides back into relaxed position away from center of sarcomere  All of the following result in muscle relaxation EXCEPT: a. Reuptake of Ca2+ by the SR b. No more ATPRigor Mortis c. No more AP d. Removal of ACh at the end plate by AChase e. Filaments sliding back to their resting position  Agents & Diseases that Affect the NMJ Alters the Release of ACh Cor continuous  Black widow spider venom explosive release of ACh*  Clostridium botulinum toxin blocks release of ACh* Blocks ACh Receptor  Curare reversibly binds to ACh receptor*  Myasthenia Gravis antibodies inactivate ACh receptor Prevents Inactivation of ACh  Organophosphates (certain irreversibly inhibits AChase* pesticides and nerve gases) * respiratory failure  Agents & Diseases that Affect the NMJ Toxin can form pores in presynaptic membrane Alters the Release of ACh  Black widow spider venom explosive release of ACh*  Clostridium botulinum toxin blocks release of ACh* Blocks ACh Receptor  Curare reversibly binds to ACh receptor*  Myasthenia Gravis antibodies inactivate ACh receptor Prevents Inactivation of ACh  Organophosphates (certain irreversibly inhibits AChase* pesticides and nerve gases) * respiratory failure  Agents & Diseases that Affect the NMJ Alters the Release of ACh  Black widow spider venom explosive release of ACh*  Clostridium botulinum toxin blocks release of ACh* Used as a medicine (Botox®) to treat chronic Blocks ACh Receptor back pain due to muscle spasms  Curare reversibly binds to ACh receptor*  Myasthenia Gravis antibodies inactivate ACh receptor Prevents Inactivation of ACh  Organophosphates (certain irreversibly inhibits AChase* pesticides and nerve gases) * respiratory failure  Agents & Diseases that Affect the NMJ Alters the Release of ACh  Black widow spider venom explosive release of ACh*  Clostridium botulinum toxin blocks release of ACh* Derivatives of curare are used to relax skeletal muscles during surgery Blocks ACh Receptor  Curare stops Contrac ten reversibly binds to ACh receptor*  Myasthenia Gravis antibodies inactivate ACh receptor Prevents Inactivation of ACh  Organophosphates (certain irreversibly inhibits AChase* pesticides and nerve gases) * respiratory failure  Agents & Diseases that Affect the NMJ Alters the Release of ACh  Black widow spider venom explosive release of ACh*  Clostridium botulinum toxin blocks release of ACh* Blocks ACh Receptor  Curare reversibly binds to ACh receptor*  Myasthenia Gravis antibodies inactivate ACh receptor Prevents Inactivation of ACh Drug neostigmine = short-term anti AChase  Organophosphates (certain irreversibly inhibits AChase* pesticides and nerve gases) * respiratory failure  Agents & Diseases that Affect the NMJ Alters the Release of ACh  Black widow spider venom explosive release of ACh*  Clostridium botulinum toxin blocks release of ACh* Blocks ACh Receptor  Curare reversibly binds to ACh receptor*  Myasthenia Gravis antibodies inactivate ACh receptor Prevents Inactivation of ACh  Organophosphates (certain irreversibly inhibits AChase* pesticides and nerve gases) Diaphragm unable to repolarize * respiratory failure  Synapse vs. NMJ Similarities  2 excitable cells separated by a narrow cleft that prevents direct transmission of electrical activity  Axon terminals store NT that are released by Ca2+- induced exocytosis of storage vesicles  NT binds to a receptor which opens membrane channels, permitting ionic movements that ∆ MP over went (beyond what  This ∆ in MP is a graded potential we  Synapse vs. NMJ Differences  Synapse: A junction between 2 neurons NMJ: Exists between a motor neuron and a skeletal muscle fiber  NMJ: *Always excitatory (EPP) Synapse: Excitatory (EPSP) or inhibitory (IPSP)  Skeletal muscle has 3 energy systems dont Need 2 know next 3 slides 1. Immediate Immediately available to support muscle contraction ATPase ATP + H2O  ADP + Pi CK CP + ADP  ATP + Cr myokinase ADP + ADP ATP + AMP Brooks et al., 2004 [CP] is 5-6x [ATP ] in resting muscle  2.Nonoxidative energy sources in muscle = B breakdown of glucose and glycogen g Glycogenolysis & Glycolysis: --rapid; fewer steps than ox phosp --no O2 --BUT, less efficient (more fuel/ATP) --lactic acid (muscle pH ) Brooks et al., 2004 Immediate and nonoxidative energy sources combined provide only a fraction of the energy that oxidative metabolism can  3. Oxidative energy sources for muscle: carbohydrates, fats and certain amino acids Ox Phosphorylation --slow; # of steps --requires O2 --BUT, highly efficient Compare: Brooks et al., 2004 Glycolysis: glucose  2 ATP Oxidative: glucose  36 ATP Oxidative: palmitate  129 ATP So, what’s the purpose of Immediate & Non-Ox pathways? } activated rapidly; produce energy at a high rate slow to activate; Brooks et al., 2004 produce energy at a low rate & Brooks et al., 2004  Skeletal Muscle Fiber Types: 1 slow, 2 fast Type Type Based on: determines speed – Speed of contraction (myosin ATPase activity) primary determient (Quick to hydrolyze ATP) – Type of metabolic pathway  ATP Prone Fatigue ! I I " ↓ ! I I Best ofboth works get ATP fast but doesn't Last long H2A-Mitochondria & Myoglobic Vascularization ,  Type I vs Type II genetie Type I Kong endurance) – Slow twitch – Oxidative metabolism – ~50% of fibers in an avg muscle Soleus: type I in everyone Ideep whin calf) Type II – Fast twitch Type IIa (~25% of fibers in an avg muscle) – Moderately high ox capacity; high glycolytic capacity Type IIx (~25% of fibers in an avg muscle) – Low ox capacity; highest glycolytic capacity  Motor Units Motor unit = 1 motor neuron + all the muscle fibers it innervates When a motor neuron is activated, all of the fibers it supplies are stimulated to contract simultaneously Erecruitment For stronger and stronger contractions, more and more motor units are recruited Sherwood ‘97  Motor Unit Recruitment Method for altering force production – Less force production: smaller motor units (type I) – More force production: larger motor units (type II) Precise, delicate * movements Powerful, coarse movements The hand muscles: Legs: a single motor a single motor unit unit contains 1,500 may contain a to 2,000 muscle dozen muscle fibers fibers  Size principle of motor neuron recruitment The CNS increases muscle force by activating additional motor units in the order of their increasing size, beginning with the smallest Recruitment order: type I, type IIa, type IIx as Intensity Increases Siz  Increased use: strength training Neural adaptations must take place before changes in muscle size -doesn't do col Musch e First It's dus to Neural Affect 1st , Early gains in strength due to neural factors (which optimize recruitment patterns) Later: increasing cross- sectional area (hypertrophy) becomes more important Schanging Siz of Pibers)  Skeletal Muscle Mechanics: contraction of whole muscles The force exerted by the same muscle can be made to vary depending on whether we pick up a: piece of paper book 50 lb. weight  Two major factors determine gradation of whole muscle tension: Conpress 1. The # of muscle fibers contracting within a muscle – # of motor units recruited – Size of the motor unit 2. The tension developed by each contracting fiber(2 Means) – Frequency of stimulation – Length-tension relationship  2. The tension developed by each contracting fiber Frequency of stimulation: repetitive stimulation  contractions of longer duration and greater tension Fiber stimulated Fiber completely a 2nd time before Smoothenoction relaxed before next AP it has relaxed  greater tension - Cat stillIn use, not stod ag a Twitch summation possible because Tetanus: Fiber stimulated Sherwood ‘97 AP = 1-2 msec so rapidly  no relaxation  2. The tension developed by each contracting fiber The length of a muscle before it contracts affects the amount of tension the muscle can generated experimental – Length-tension relationship: The relationship between initial length and tension can be explained by the # of cross-bridges that can be formed during the contraction Actin sites and X-bridges no longer match up Muscle stretched to 70% - # actin sites exposed to X-bridges longer than lo, no X-bridge -Thick filaments forced vs Z lines activity, no contraction  Types of Muscle Contraction Isometric (same length) contraction /plants , well sits , Skiing – Muscle produces force but does not change length – Joint angle does not change – Myosin cross-bridges form and recycle, no sliding; static 12Types spicky Isotonic phase) (same tension) contraction up – Muscle produces force and changes length – Joint movement produced; dynamic  Isotonic Contraction Subtypes Concentric contraction – Muscle shortens while producing force – Most familiar type of contraction – Sarcomere shortens, filaments slide toward center possibly less stable Eccentricdamage contraction (couses most Interacting while Lengthen – Muscle lengthens while producing force – Cross-bridges form but sarcomere lengthens – Example: lowering heavy weight H E C B d A fo C  Smooth Muscle: Use and Unique Properties Location Walls of hollow organs (gallbladder, uterus, bladder) Tubes (GI tract, blood vessels) SEM of an arteriole All smooth muscle exhibits tone (basal tension); contractions superimposed on tone Maintains shape and pushes contents along  Contraction – Slower and longer contraction vs sk muscle Generates comparable force using More Economic 300 times less ATP Gives up speed for ability to adapt and adjust – Responds to variety of stimuli: nerves, hormones, stretch, etc. – Latch state possible: prolonged contraction w/o input of ATP Diverse Functions  Structure compared to skeletal muscle fibers Smooth muscle lacks – Sarcomeres (no striations) – Troponin – T-tubules Smooth muscle has – Dense bodies (analogous to Z lines) anchors actin; held in place by intermediate filaments – Tropomyosin, but role unclear – Caveolae: indentations in sarcolemma May act like T tubules – SR, but not well developed  Excitation-Contraction Coupling RMP is relatively low (-50 to -60 mV) Long AP = 10-50 ms (vs 2-3 ms in sk muscle) – No voltage-gated Na+ channels at “motor end plate” – Voltage gated Ca2+ channels (dihydropyridine) 3 Dihydropyridine Receptors Skeletal: voltage sensor Cardiac: voltage-dependent Ca2+ channel; only lets a little Ca2+ in Smooth: voltage-dependent Ca2+ channel; lets in enough Ca2+ for AP  Ca2+ Triggers Contraction Role of Ca2+: the state of the thick filaments (not thin filaments) are affected by Ca2+ Where the Ca2+ comes from: – Most from outside the cell Depolarization  voltage-gated Ca2+ channels open NTs, hormones, etc. open Ca2+ channels – A little Ca2+ is released by the SR Smooth Muscle Contraction: Mechanism Extracellular Ca2+ enters via: Voltage-gated channels (aka L-type, aka DHPR) Ligand-gated channel Responds to nerves, Stretch-activated channel hormones, stretch Chemical activation: Ca2+ binds to calmodulin, leading to activation of myosin light chain kinase (MLCK). MLCK phosphorylates the light chain of myosin. When myosin is phosphorylated, X-bridges can form and break repeatedly Smooth: myosin is “off” Skeletal: myosin always “on” Smooth Muscle Relaxation: Mechanism Relaxation is a result of: Removal of the contractile stimulus (ed [Ca2+]i) or Direct action of a substance that inhibits the contractile mechanism (ed myosin phosphatase activity) + EPI + cGMP + The ratio of MLCK and MP is important! NO  Pharmacological Relaxation EPI + L-type Ca2+ channel blocker  in cAMP or cGMP cAMP (EPI via β2) inhibits MLCK + cGMP + – EPI used in the treatment of bronchospasm of asthma NO cGMP (nitroglycerin) stimulates myosin phosphatase – Nitroglycerin (converted to nitric oxide in the body) used to relax coronary arteries – Sildenafil “-” cGMP phosphodiesterases for ED FYI: Sexual stimulation  production and release of NO  activates guanylate cyclase  production of cyclic guanosine monophosphate (cGMP)  smooth muscle relaxation   BF  Tonic Contraction How can vascular smooth muscle (think aorta) endure 60 “insults” per minute & sustain BP w/o expending a lot of ATP? – Deposit collagen? No - too stiff! – Develop force Smooth muscle has a way for cross bridges to remain attached, cycle slowly and consume less ATP  Tonic Contraction Mechanism: Dephosphorylation of myosin while it is still attached to actin – Dephosphorylated  ATPase activity decreases More difficult to release myosin heads from actin; slow X-bridge cycling (low ATP use)  Smooth muscle summary Involuntary, non-striated muscle associated with blood vessels and visceral organs Overlapping myofilaments – Sliding filaments generate force Increased intracellular Ca2+ regulates myosin Ca2+ increased through: – Mechanically gated Ca2+ channels – Ligand gated Ca2+ channels (ANS, hormones, paracrine) – Voltage gated Ca2+ channels Capable of phasic contraction and tonic contraction