2. Chapter 9 Motor System - 1 Muscle Contraction and Motor Unit

6. Content Skeletal Muscle Contraction Motor Unit

7. Reference – Text Book P160-163 P56 – 70 P464 P85 – 91 P673 - 674

8. Section I Skeletal Muscle Contraction Signal Transmission Through Neuromuscular Junction Molecular Mechanism of Muscle Contraction Factors that Affect the Efficiency of Muscle Contraction

9. Part I Signal Transmission Through the Neuromuscular Junction

10. 9 Skeletal Muscle Innervation

11. 10 Illustration of the Neuromuscular Junction (NMJ)

12. 11 New Ion Channel Players  Voltage-gated Ca 2+ channel  in presynaptic nerve terminal  mediates neurotransmitter release  Nicotinic Acetylcholine Receptor Channel  in muscle neuromuscular junction (postsynaptic membrane, or end plate)  mediates electrical transmission from nerve to muscle

13. 12 Neuromuscular Transmission Skeletal Muscle Myelin Axon Axon Terminal

14. 13 Neuromuscular Transmission: Transmission: Step by Step Nerve action potential invades axon terminal - + - - - - - - + + + + + + + - - - + + Depolarization of terminal opens Ca channels Look here +

15. 14 K+K+ Outside Inside Na + K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ ACh Ca 2+ induces fusion of vesicles with nerve terminal membrane. ACh is released and diffuses across synaptic cleft. ACh ACh binds to its receptor on the postsynaptic membrane Binding of ACh opens channel pore that is permeable to Na + and K +. Na + K+K+ Muscle membrane Nerve terminal Ca 2+

16. 15 End Plate Potential (EPP ，终板电位 ) Outside Inside Muscle membrane Presynaptic terminal Muscle Membrane Voltage (mV) Time (msec) -90 mV VKVK V Na 0 Threshold Presynaptic AP EPP The movement of Na + and K + depolarizes muscle membrane potential (EPP) ACh Receptor Channels Voltage-gated Na Channels Inward Rectifier K Channels

17. 16 Meanwhile... Outside Inside ACh ACh unbinds from its receptor Muscle membrane ACh so the channel closes ACh Nerve terminal ACh is hydrolyzed by AChE into Choline and acetate CholineAcetate Choline is taken up into nerve terminal Choline Choline resynthesized into ACh and repackaged into vesicle ACh

18. 17 Structural Reality

19. 18 Neuromuscular Transmission  Properties of neuromuscular junction  1:1 transmission:  An unidirectional process  Has a time delay. 20nm/0.5-1ms  easily affect by drugs and some factors  The NMJ is a site of considerable clinical importance

20. 19 Clinical Chemistry Ach is the natural agonist at the neuromuscular junction. Tubocurarine is the primary paralytic ingredient in curare. Tubocurarine competes with ACh for binding to receptor- but does not open the pore. So tubocurarine is a neuromuscular blocking agent. Tubocurarine and other, related compounds are used to paralyze muscles during surgery. Carbachol is a synthetic agonist not hydrolyzed by acetylcholinesterase. Carbachol and related compounds are used clinically for GI disorders, glaucoma, salivary gland malfunction, etc. Suberyldicholine is a synthetic neuromuscular agonist. Related compounds are useful in the neuroscience research

21. 20 Anticholinesterase Agents  Anticholinesterase (anti-ChE 胆碱酯酶抑制剂 ) agents inhibit acetylcholinesterase （乙酰胆 碱酯酶）  prolong excitation at the NMJ

22. 21 1. Normal: ACh Choline + Acetate AChE 2. With anti - AchE: ACh Choline + Acetate anti - AChE Anticholinesterase Agents

23. 22 Uses of anti-ChE agents  Clinical applications (Neostigmine, 新斯的明, Physostigmine 毒扁豆碱 )  Insecticides (organophosphate 有机磷酸酯 )  Nerve gas (e.g. Sarin 沙林，甲氟膦酸异丙酯。一 种用作神经性毒气的化学剂 ))

24. 23 NMJ Diseases  Myasthenia Gravis （重症肌无力）  Autoimmunity to ACh receptor  Fewer functional ACh receptors  Low “safety factor” for NM transmission  Lambert-Eaton syndrome （ 兰伯特 - 伊顿综 合征 ， 癌性肌无力综合征 ）  Autoimmunity directed against Ca 2 ＋ channels  Reduced ACh release  Low “safety factor” for NM transmission

25. Prat II Molecular Mechanism of Muscle Contraction

26. 25 Structure of Skeletal Muscle: Microstructure  Sarcolemma （肌管系统）  Transverse (T) tubule  Longitudinal tubule (Sarcoplasmic reticulum, SR 肌浆网 )  Myofibrils （肌原纤维）  Actin 肌动蛋白 (thin filament)  Troponin （肌钙蛋白）  Tropomyosin （原肌球蛋白）  Myosin 肌球蛋白 (thick filament)

27. 26 Within the Sarcoplasm  Transverse tubules （横管）  Sarcoplasmic reticulum - Storage sites for calcium  Terminal cisternae - Storage sites for calcium Triad （三联管）

28. 27 Sarcomeres  bundle of alternating thick and thin filaments  join end to end to form myofibrils  Thousands per fiber, depending on length of muscle  Alternating thick and thin filaments create appearance of striations

29. 28

30. 29  Thick filament: Myosin ( 肌球蛋白， head and tail)  Thin filament: Actin 肌动蛋白, Tropomyosin 原肌 球蛋白, Troponin ( 肌钙蛋白 calcium binding site)

31. 30 Molecular Mechanism of Muscular Contraction  The sliding filament model 肌丝滑行  Muscle shortening is due to movement of the actin filament over the myosin filament  Reduces the distance between Z-lines

32. 31 The Sliding Filament Model of Muscle Contraction

33. 32 Changes in the appearance of a Sarcomere during the Contraction of a Skeletal Muscle Fiber

34. 33 Energy for Muscle Contraction  ATP is required for muscle contraction  Myosin ATPase breaks down ATP as fiber contracts

35. 34 Nerve Activation of Individual Muscle Cells (cont.)

36. 35  Action potential along T-tubule causes release of calcium from cisternae of TRIAD  Cross-bridge cycle Excitation/contraction coupling

37. Begin cycle with myosin already bound to actin

38. 37 1. Myosin heads form cross bridges  Myosin head is tightly bound to actin in rigor state  Nothing bound to nucleotide binding site

39. 38 2. ATP binds to myosin  Myosin changes conformation, releases actin

40. 39 3. ATP hydrolysis  ATP is broken down into:  ADP + P i (inorganic phosphate)  Both ADP and P i remain bound to myosin

41. 40 4. Myosin head changes conformation  Myosin head rotates and binds to new actin molecule  Myosin is in high energy configuration

42. 41 5. Power stroke  Release of P i from myosin releases head from high energy state  Head pushes on actin filament and causes sliding  Myosin head splits ATP and bends toward H zone. This is Power stroke.

43. 42 6. Release of ADP  Myosin head is again tightly bound to actin in rigor state  Ready to repeat cycle

44. 43 THE CROSS-BRIDGE CYCLE ATP ADP + P i A M A – M  ATP A M ADP P i A + M  ADP  P i Relaxed state Crossbridge energised Crossbridge attachment Tension develops Crossbridge detachment Ca 2+ present A, Actin; M, Myosin

45. 44 Cross Bridge Cycle

46. 45 Rigor mortis  Myosin cannot release actin until a new ATP molecule binds  Run out of ATP at death, cross-bridges never release

47. 46 Many contractile cycles occur asynchronously during a single muscle contraction Need steady supply of ATP!

48. 47 Regulation of Contraction  Tropomyosin blocks myosin binding in absence of Ca 2+  Low intracellular Ca 2+ when muscle is relaxed

49. 48 Ca +2 binds to troponin during contraction  Troponin-Ca 2+ pulls tropomyosin, unblocking myosin-binding sites  Myosin-actin cross-bridge cycle can now occur

50. 49 How does Ca 2+ get into cell?  Action potential releases intracellular Ca 2+ from sarcoplasmic reticulum (SR)  SR is modified endoplasmic reticulum  Membrane contains Ca 2+ pumps to actively transport Ca 2+ into SR  Maintains high Ca 2+ in SR, low Ca 2+ in cytoplasm

51. 50 Ca 2+ Controls Contraction Ca 2+ Channels and Pumps  Release of Ca 2+ from the SR triggers contraction  Reuptake of Ca 2+ into SR relaxes muscle

52. Structures involved in EC coupling - Skeletal Muscle - out in voltage sensor? junction foot sarcoplasmic reticulum sarcolemma T-tubule

53. 52 Dihydropyridine （ DHP, 双氢吡啶） Receptor In t-tubules of heart and skeletal muscle  Nifedipine and other DHP-like molecules bind to the "DHP receptor" in t-tubules  In heart,  a voltage-gated Ca 2+ channel  In skeletal muscle,  voltage-sensing protein  undergoes voltage-dependent conformational changes

54. 53 Ryanodine ( 利阿诺定 ) Receptor The "foot structure" in terminal cisternae of SR  Foot structure is a Ca 2+ channel of unusual design  Conformation change or Ca 2+ -channel activity of DHP receptor  gates the ryanodine receptor,  opening and closing Ca 2+ channels  Many details are yet to be elucidated!

55. out in voltage sensor (DHP receptor) junctional foot (ryanodine receptor) sarcoplasmic reticulum sarcolemma T-tubule Skeletal muscle  The AP:  moves down the t-tubule  voltage change detected by DHP （双氢吡啶） receptors  DHP receptor is essentially a voltage-gated Ca channel  is communicated to the ryanodine receptor which opens to allow Ca out of SR  activates contraction

56. Cardiac muscle  The AP:  moves down the t-tubule  voltage change detected by DHP receptors (Ca 2+ channels) which opens to allow small amount of (trigger) Ca 2+ into the fibre  Ca 2+ binds to ryanodine receptors which open to release a large amount of (activator) Ca 2+ (CACR)  Thus, calcium, not voltage, appears to trigger Ca 2+ release in Cardiac muscle! out in voltage sensor & Ca channel (DHP receptor) junctional foot (ryanodine receptor) sarcoplasmic reticulum sarcolemma T-tubule

57. Comparison Skeletal  The trigger for SR release appears to be voltage (Voltage Activated Calcium Release- VACR)  The t-tubule membrane has a voltage sensor (DHP receptor)  The ryanodine receptor is the SR Ca release channel  Ca 2+ release is proportional to membrane voltage Cardiac  The trigger for SR release appears to be calcium (Calcium Activated Calcium Release - CACR)  The t-tubule membrane has a Ca 2+ channel (DHP receptor)  The ryanodine receptor is the SR Ca release channel  The ryanodine receptor is Ca- gated & Ca release is proportional to Ca 2+ entry

58. 57 Summary: Excitation-Contraction Coupling

59. Part III Factors that Affect the Efficiency of Muscle Contraction

60. 59 Tension 张力 and Load 负荷  The force exerted on an object by a contracting muscle is known as tension.  The force exerted on the muscle by an object (usually its weight) is termed load.  According to the time of effect exerted by the loads on the muscle contraction the load was divided into two forms, preload and afterload.

61. 60 Preload 前负荷  Preload  load on the muscle before muscle contraction.  Determines the initial length of the muscle before contraction.  Initial length  the length of the muscle fiber before its contraction.  positively proportional to the preload.

62. 61 The Effect of Sarcomere Length on Tension The Length – Tension Curve Concept of optimal length

63. 62 Types of Contractions I  Twitch 单收缩 : a brief mechanical contraction of a single fiber produced by a single action potential at low frequency stimulation is known as single twitch.  Tetanus 强直收缩 : summation of twitches that occurs at high frequency stimulation

64. 63 Effects of Repeated Stimulations Figure 10.15

65. 64 1/sec5/sec10/sec50/sec

66. 65 Afterload 后负荷  Afterload  load on the muscle after the beginning of muscle contraction.  reverse force that oppose the contractile force caused by muscle contraction.  does not change the initial length of the muscle  prevent muscle from shortening

67. 66  Afterload is resistance  Isometric 等长  Length of muscle remains constant. Peak tension produced. Does not involve movement  Isotonic 等张  Length of muscle changes. Tension fairly constant. Involves movement at joints  Resistance and speed of contraction inversely related Types of Contractions (II)

68. 67 Isotonic and Isometric Contractions

69. 68 Resistance and Speed of Contraction

70. 69

71. 70 Muscle Power Maximal power occurs where the product of force (P) and velocity (V) is greatest (P=FV) X Max Power= 4.5units

72. Section 2. Motor Unit a single motor neuron (  motor) and all (extrafusal) muscle fibers it innervates the physiological functional unit in muscle (not the cell) All cells in motor unit contract synchronously

73. Extrafusal Muscle: innervated by Alpha motor neuron Intrafusal muscle: innervated by Gamma motor neurons

74. Motor units and innervation ratio Purves Fig. 16.4 Innervation ratio Fibers per motor neuron Extraocular muscle 3:1 Gastrocnemius 2000:1 （腓肠肌）

75. The muscle cells of a motor unit are not grouped, but are interspersed among cells from other motor units The coordinated movement needs the activation of several motors

77. Overview - organization of motor systems Motor Cortex Brain Stem Spinal Cord Skeletal muscle  -motor neuron Final common pathway

78. Final common path -  -motor neuron (-) muscle fibers (+) (-) (+) axon hillock motor nerve fiber NM junction Schwann cells Receptors? acetylcholine esterase Transmitter?

79. Final Common Pathway, a motor pathway consisting of the motor neurons by which nerve impulses from many central sources pass to a muscle in the periphery