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“Walk-Along” Theory

“Walk-Along” Theory. Figure 6-7; Guyton & Hall. Chapter 6:. Contraction of Skeletal Muscle. Slides by Thomas H. Adair, PhD. Anatomy of Skeletal Muscle. Gross organization:. Figure 6-1; Guyton & Hall. Cellular Organization. Muscle fibers single cells multinucleated surrounded by the

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“Walk-Along” Theory

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  1. “Walk-Along” Theory Figure 6-7; Guyton & Hall

  2. Chapter 6: Contraction of Skeletal Muscle Slides by Thomas H. Adair, PhD

  3. Anatomy of Skeletal Muscle Gross organization: Figure 6-1; Guyton & Hall

  4. Cellular Organization • Muscle fibers • single cells • multinucleated • surrounded by the • sarcolemma • Myofibrils • contractile elements • surrounded by the • sarcoplasm Cellular organelles - lie between myofibrils (mitochondria, sarcoplasmic reticulum etc.) Figure 6-1; Guyton & Hall

  5. Molecular Organization Figure 6-1; Guyton & Hall

  6. sarcomere A band H zone I band M line Z disc The Sarcomere thick filament (myosin) thin filament (actin) titin (filamentous structural protein)

  7. “Sliding Filament” Mechanism Contraction results from the sliding action of interdigitating actin and myosin filaments RELAXED: CONTRACTED:

  8. The Actin Filament • the I band filament • tethered at one end at the Z disc • 1mm long: v. uniform nebulin forms guide for synthesis Figure 6-6; Guyton & Hall • tropomyosin • covers active sites • prevents interaction • with myosin • F-actin • double-stranded helix • composed of polymerized G-actin • ADP bound to each G-actin • (active sites) • myosin heads bind to active sites • troponin • I - binds actin • T - binds tropomyosin • C - binds Ca2+

  9. The Myosin Molecule: • two heavy chains (MW 200,000) • four light chains (MW 20,000) • “head” region - site of ATPase activity Figure 6-5; Guyton & Hall

  10. Mechanism of Muscle Contraction Theory: Binding of Ca2+ to troponin results in a conformational change in tropomyosin that “uncovers” the active sites on the actin molecule, allowing for myosin to bind.

  11. “Sliding Filament” Mechanism Contraction results from the sliding action of interdigitating actin and myosin filaments RELAXED: CONTRACTED:

  12. Neuromuscular Transmission -The Neuromuscular Junction - Figure 7-1; Guyton & Hall • Specialized synapse between a motoneuron and a • muscle fiber • Occurs at a structure on the muscle fiber called the motor • end plate(usually only one per fiber)

  13. Neuromuscular Junction (nmj) Synaptic trough:invagination in the motor endplate membrane • Synaptic cleft: • 20-30 nm wide • contains large quantities of acetylcholinesterase (AChE) • Subneural clefts: • increase the surface area of the post-synaptic membrane • Ach gated channels at tops • Voltage gated Na+ channel in bottom half Figure 7-1; Guyton & Hall

  14. The Motoneuron – vesicle formation • Synaptic vesicles:are formed from budding Golgi and are • transported to the terminal by axoplasm “streaming” • (~300,000 per terminal) • Acetylcholine(ACh) is formed in the cytoplasm and is • transported into the vesicles (~10,000 per) • Ach filled vesicles occasionally fuse with the post-synaptic • membrane and release their contents. This causes • miniature end-plate potentials in the post-synaptic • membrane.

  15. AP Ca2+ 1 3 2 The Motoneuron - ACh Release • AP begins in the ventral horn of spinal cord. • Local depolarization opens voltage-gated Ca2+ channels. • An increase incytosolic Ca2+ triggers the fusion of ~125 synaptic vesicles with the pre-synaptic membrane and release of ACh (exocytosis).

  16. ACh Release - details • Ca2+ channels are localized around linear structures on the pre-synaptic membrane called dense bars. • Vesicles fuse with the membrane in the region of the dense bars. • Ach receptors located at top of subneural cleft. • Voltage gated Na+ channels in bottom half of subneural cleft. Figure 7-2; Guyton & Hall

  17. ACh released into the neuromuscular junction binds to, and opens, nicotinic ACh receptor channels on the muscle fiber membranes (Na+, K+, Ca2+). nAChr Na channel End Plate Potential and Action Potential - at the motor endplate - • Opening of nACh receptor channels produces an end plate potential, which will normally initiate an AP if the local spread of current is sufficient to open voltage sodium channels. mV 40 0 -40 -80 • What terminates the process? acetylcholinesterase 0 1530 45 60 75 mSec

  18. “normal” botulinum toxin curare Drug Effects on End Plate Potential - Inhibitors - • Curariform drugs (D-turbocurarine) • block nicotinic ACh • channels by competing • for ACh binding site • reduces amplitude of • end plate potential therefore, no AP threshold • Botulinum toxin • decreases the release of Ach • from nerve terminals • insufficient stimulus to initiate • an AP Figure 7-4; Guyton & Hall

  19. Drug Effects on End Plate Potential - Stimulants - • ACh-like drugs(methacholine, carbachol, nicotine) • bind and activate nicotinic ACh receptors • not destroyed by AChE – prolonged effect • Anti-AChE(neostigmine, physostigmine, diisopropyl fluorophosphate or “nerve gas”) • block the degradation of ACh • prolong its effect

  20. Myasthenia Gravis Incidence / symptoms: • paralysis - lethal in extreme cases when respiratory • muscles are involved • 2 per 1,000,000 people / year Cause: • autoimmune disease characterized by the presence of • antibodies against the nicotinic ACh receptor which destroys • them • weak end plate potentials • Treatment: • usually ameliorated by anti-AChE (neostigmine) • increases amount of ACh in nmj

  21. Lambert-Eaton Myasthenic Syndrome Incidence / symptoms: • 1 per 100,000 people / year • 40% also have small cell lung cancer • muscle weakness/paralysis Cause: • LEMS results from an autoimmune attack against voltage-gated • calcium channels on the presynaptic motor nerve terminal. • weak end plate potentials • Treatment: • can be treated with anti-AChE (neostigmine) • increases amount of ACh in nmj

  22. Excitation-Contraction Coupling Transverse tubule / SR System • T-tubules: • Invaginations of the sarcolemma • filled with extracellular fluid • Penetrate the muscle fiber, branch • and form networks • Transmit AP’s deep into the • muscle fiber • Sarcoplasmic Reticulum: • terminal cisternae and longitudinal tubules • terminal cisternae form • junctional “feet” adjacent to the T- • tubule membrane • intracellular storage compartment • for Ca2+ Figure 7-5; Guyton & Hall

  23. Arrangement of T-tubules to Myofibrils - Skeletal muscle vs cardiac muscle - • Vertebrate skeletal muscle: • Two T-tubule networks per • sarcomere • Located near the ends of the • myosin filaments (zone of overlap) • Cardiac muscle(and lower animals): • Single T-tubule network per • sarcomere • Located at the level of the Z disc Figure 7-5; Guyton & Hall

  24. dihydropyridine receptor: it’s a voltage sensor Terminal cisterne of SR ryanodine Ca2+ release channel • EC Coupling - the “Triad” • the junction between two terminal • cisternae and a T-tubule T-tubule

  25. EC Coupling – how it works (skeletal muscle) • Sequence of Events: • AP moves along T-tubule • The voltage change is sensed by the DHP receptor. • Is communicated to the ryanodine receptor which opens. (VACR) • Contraction occurs. • Calcium is pumped back into SR. Calcium binds to calsequestrin to facilitate storage. • Contraction is terminated. AP Ca2+ pump calsequestrin

  26. Why is so much heat generated? Clinical Oddity: Malignant Hyperthermia Symptoms: • spontaneous combustion • skeletal muscle rigidity • lactic acidosis (hypermetabolism) Cause: • triggered by anesthetics (halothane) • familial tendency - can be tested for by muscle biopsy • constant leak of SR Ca2+through ryanodine receptor Ca pump • Our bodies are only about 45% energy efficient. 55% of the energy appears as heat. ATP

  27. Muscle Mechanics

  28. Normal operating range 1 0.5 0 0 1 2 3 4 sarcomere length (mm) Tension as a Function of Sarcomere Length • Stress is used to compare tension (force) generated by different sized muscles • stress = force/cross-sectional area of muscle; units kg/cm2) • In skeletal muscle, maximal active stress is developed at normal resting length ~ 2 mm • At longer lengths, stress declines - • At shorter lengths stress also declines - • Cardiac muscle normally operates at lengths below optimal length - active stress (tension)

  29. Myoplasmic [Ca2+] Fused tetanus Force AP Time (1 second) Frequency Summation of Twitches and Tetanus • Myoplasmic Ca2+ falls (initiating relaxation) before development of maximal contractile force • If the muscle is stimulated before complete relaxation has occurred the new twitch will sum with the previous one etc. • If action potential frequency is sufficiently high, the individual contractions are not resolved and a ‘fused tetanus’ contraction is recorded.

  30. large diameter Motor Unit: A collection of muscle fibers innervated by a single motor neuron • All fibers are same type (fast or • slow) in a given motor unit • Small motor units(eg,larnyx, extraocular) • as few as 10 fibers/unit • precise control • rapid reacting • Large motor units(eg, quadriceps muscles) • as many as 1000 fibers/unit • coarse control • slower reacting • Motor units overlap, which provides • coordination • Not a good relation between fiber type • and size of motor unit

  31. Relationship of Contraction Velocity to Load • no afterload: • maximum velocity at • minimum load A • increased afterload: • contraction velocity • decreases B contraction velocity is zero when afterload = max force of contraction A: larger, faster muscle (white muscle) B: smaller, slower muscle (red muscle)

  32. Types of Skeletal Muscle- speed of twitch contraction - • Speed of contraction determined by Vmax of myosin ATPase. • High Vmax(fast, white) • rapid cross bridge cycling • rapid rate of shortening (fast fiber) • Low Vmax (slow, red) • slow cross bridge cycling • slow rate of shortening (slow fiber) • Most muscles contain both types of fiber but proportions differ • All fibers in a particular motor unit will be of the same type i.e., fast or slow. Figure 6-12; Guyton & Hall

  33. Types of Skeletal Muscle - resistance to fatigue - Slow (red muscle) • fast and slow fibers show different resistance to fatigue • slow fibers • oxidative • small diameter • high myoglobin content • high capillary density • many mitochondria • low glycolytic enzyme content • fast fibers • glycolytic force (% initial) Fast (white muscle) 0 5 60 time (min)

  34. What do the different types do? Fast-twitch slow-twitch Marathon 18% 82% Runners Swimmers 26 74 Average 55 45 man Weight 55 45 Lifters Sprinters 64 37 Jumpers 63 37 • Fast, slow and intermediate twitch type muscle can be identified by histochemistry. • In any muscle there will be a mixture of slow and fast fibers. • Motor units containing slow fibers will be recruited first to power normal contractions. • Fast fibers help out when particularly forceful contraction is required. • Different people have different proportions of these types. • There is little evidence that training alters these proportions in humans.

  35. left AT Conversion of Fiber Type - fast to slow - • Anterior tibialis – • Predominantly fast twitch (upper) • Stains light: few mitochondria • Few, small capillaries • Large fibers • Electrical stimulation (10 Hz) via motor nerve (60 days) • Stimulating fast muscle at the pace of a slow muscle converts fast twitch fibers to predominantly slow twitch fibers (lower) • Stains dark: more mitochondria • Many, large capillaries • Larger fibers right AT

  36. Muscle Contraction - force summation Force summation:increase in contraction intensity as a result of the additive effect of individual twitch contractions (1) Multiple fiber summation:results from an increase in the number of motor units contracting simultaneously (fiber recruitment) Figure 6-13; Guyton & Hall (2) Frequency summation:results from an increase in the frequency of contraction of a single motor unit

  37. hypertrophy lengthening hyperplasia Muscle Remodeling - growth • Hypertrophy (common, weeks) • Caused by near maximal force development (eg. weight lifting) • Increase in actin and myosin • Myofibrils split • Hyperplasia (rare) • Formation of new muscle fibers • Can be caused by endurance training • Hypertrophy and hyperplasia • Increased force generation • No change in shortening capacity or velocity of contraction • Lengthening (normal) • Occurs with normal growth • No change in force development • Increased shortening capacity • Increased contraction velocity

  38. atrophy atrophy with fiber loss Muscle Remodeling - atrophy • Causes of atrophy • Denervation/neuropathy • Tenotomy • Sedentary life style • Plaster cast • Space flight (zero gravity) • Muscle performance • Degeneration of contractile proteins • Decreased max force of contraction • Decreased velocity of contraction • Atrophy with fiber loss • Disuse for 1-2 years • Very difficult to replace lost fibers weeks months/ years

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