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1 LIU Chuan Yong 刘传勇 Institute of Physiology Medical School of SDU Tel 88381175 (lab) 88382098 (office) Website:

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Presentation on theme: "1 LIU Chuan Yong 刘传勇 Institute of Physiology Medical School of SDU Tel 88381175 (lab) 88382098 (office) Website:"— Presentation transcript:


2 1 LIU Chuan Yong 刘传勇 Institute of Physiology Medical School of SDU Tel 88381175 (lab) 88382098 (office) Email: Website:

3 Section 4 Muscle Contraction

4 3 Classification of the Muscle  According to the structure: Striated Muscle, Smooth Muscle  According to the nerve innervation: Voluntary Muscle, Involuntary Muscle  According to the Function: Skeletal Muscle, Cardiac Contraction, Smooth Muscle

5 4 Skeletal MuscleCardiac Muscle Smooth Muscle

6 I Signal Transmission Through the Neuromuscular Junction

7 6 Skeletal Muscle Innervation

8 7 Illustration of the Neuromuscular Junction (NMJ)

9 8 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

10 9 Nerve Terminal Ca 2+ channels  Structurally similar to Na + channels  Functionally similar to Na + channels except  activation occurs at more positive potentials  activation and inactivation much slower than Na + channels

11 10 Neuromuscular Transmission Skeletal Muscle Myelin Axon Axon Terminal

12 11 Neuromuscular Transmission: Transmission: Step by Step Nerve action potential invades axon terminal - + - - - - - - + + + + + + + - - - + + Depolarization of terminal opens Ca channels Look here +

13 12 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+

14 13 End Plate Potential (EPP) 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

15 14 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

16 15 Structural Reality

17 16 Neuromuscular Transmission  Properties of neuromuscular junction  1:1 transmission: A chemical transmission which is designed to assure that every presynaptic action potential results in a postsynaptic one  An unidirectional process  Has a time delay. 20nm/0.5-1ms  Is easily affect by drugs and some factors  The NMJ is a site of considerable clinical importance

18 17 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

19 18 Anticholinesterase Agents  Anticholinesterase (anti-ChE) agents inhibit acetylcholinesterase (乙酰胆碱酯 酶)  prolong excitation at the NMJ

20 19 1. Normal: ACh Choline + Acetate AChE 2. With anti - AchE: ACh Choline + Acetate anti - AChE Anticholinesterase Agents

21 20 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 ))

22 21 Sarin and Sarin and Aum Shinrikyo( 奥姆真理教 )  Aum Shinrikyo( 奥姆真理教 ) is a Japanese religious cult obsessed with the apocalypse (启示,天启).  The previously obscure group became infamous in 1995 when some of its members released deadly sarin nerve gas into the Tokyo subway system,  killing 12 people and sending more than 5,000 others to hospitals.

23 22 Sarin  Sarin, which comes in both liquid and gas forms,  is a highly toxic and volatile nerve agent developed by Nazi scientists in Germany in the 1930s.  Chemical weapons experts say that sarin gas is 500 times more toxic than cyanide (氢化物) gas.

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 II Microstructure of Skeletal Muscle

26 25 Skeletal Muscle  Human body contains over 400 skeletal muscles  40-50% of total body weight  Functions of skeletal muscle  Force production for locomotion and breathing  Force production for postural support  Heat production during cold stress

27 26  Fascicles: bundles, CT(connective tissue) covering on each one  Muscle fibers: muscle cells

28 27 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)

29 28 Within the sarcoplasm  Transverse tubules  Sarcoplasmic reticulum -Storage sites for calcium  Terminal cisternae - Storage sites for calcium Triad (三 联管)

30 29 Microstructure of Skeletal Muscle (myofibril)

31 30 Sarcomeres  Sarcomere 肌小节 : bundle of alternating thick and thin filaments  Sarcomeres join end to end to form myofibrils  Thousands per fiber, depending on length of muscle  Alternating thick and thin filaments create appearance of striations

32 31

33 32  Myosin head is hinged  Bends and straightens during contraction Myosin 肌球蛋白

34 33 Thick filaments (myosin)  Bundle of myosin proteins shaped like double- headed golf clubs  Myosin heads have two binding sites  Actin binding site forms cross bridge  Nucleotide binding site binds ATP (Myosin ATPase)  Hydrolysis of ATP provides energy to generate power stroke

35 34 Thin filaments 原肌球蛋白肌钙蛋白 肌动蛋白

36 35 Thin filaments (actin)  Backbone: two strands of polymerized globular actin – fibrous actin  Each actin has myosin binding site  Troponin  Binds Ca 2+ ; regulates muscle contraction  Tropomyosin  Lies in groove of actin helix  Blocks myosin binding  sites in absence of Ca 2+

37 36  Thick filament: Myosin (head and tail)  Thin filament: Actin, Tropomyosin, Troponin (calcium binding site)

38 37 III Molecular Mechanism of Muscular Contraction  The sliding filament model  Muscle shortening is due to movement of the actin filament over the myosin filament  Reduces the distance between Z-lines

39 38 The Sliding Filament Model of Muscle Contraction

40 39 Changes in the appearance of a Sarcomere during the Contraction of a Skeletal Muscle Fiber

41 40 Cross-Bridge Formation in Muscle Contraction

42 41 Energy for Muscle Contraction  ATP is required for muscle contraction  Myosin ATPase breaks down ATP as fiber contracts

43 42 Nerve Activation of Individual Muscle Cells (cont.)

44 43  Action potential along T-tubule causes release of calcium from cisternae of TRIAD  Cross-bridge cycle Excitation/contraction coupling

45 Begin cycle with myosin already bound to actin

46 45 1. Myosin heads form cross bridges  Myosin head is tightly bound to actin in rigor state  Nothing bound to nucleotide binding site

47 46 2. ATP binds to myosin  Myosin changes conformation, releases actin

48 47 3. ATP hydrolysis  ATP is broken down into:  ADP + P i (inorganic phosphate)  Both ADP and P i remain bound to myosin

49 48 4. Myosin head changes conformation  Myosin head rotates and binds to new actin molecule  Myosin is in high energy configuration

50 49 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.

51 50 6. Release of ADP  Myosin head is again tightly bound to actin in rigor state  Ready to repeat cycle

52 51 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

53 52 Cross Bridge Cycle

54 53 Rigor mortis  Myosin cannot release actin until a new ATP molecule binds  Run out of ATP at death, cross-bridges never release

55 54 Many contractile cycles occur asynchronously during a single muscle contraction Need steady supply of ATP!

56 55 Regulation of Contraction  Tropomyosin blocks myosin binding in absence of Ca 2+  Low intracellular Ca 2+ when muscle is relaxed

57 56 Ca +2 binds to troponin during contraction  Troponin-Ca +2 pulls tropomyosin, unblocking myosin-binding sites  Myosin-actin cross-bridge cycle can now occur

58 57 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

59 The action potential triggers contraction  How does the AP trigger contraction?  This question has the beginning (AP) and the end (contraction) but it misses lots of things in the middle!  We should ask:  how does the AP cause release of Ca from the SR, so leading to an increase in [Ca] i ?  how does an increase in [Ca] i cause contraction?

60 Z disc A band (myosin) I band (actin) Z disc M line Z disc sarcoplasmic reticulum t-tubules junctional feet Triad  Contractile proteins in striated muscle are organised into sarcomeres  T-tubules and sarcoplasmic reticulum are organised so that Ca release is directed toward the regulatory (Ca binding) proteins  The association of a t-tubule with SR on either side is often called a ‘triad’ (三联管) (tri meaning three) Structures involved in EC coupling

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

62 61 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  So how is calcium released in response to nerve impulses?  Answer has come from studies of antagonist molecules that block Ca 2+ channel activity

63 62

64 63 Dihydropyridine 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, DHP receptor is a voltage-gated Ca 2+ channel  In skeletal muscle, DHP receptor is apparently a voltage-sensing protein and probably undergoes voltage-dependent conformational changes

65 64 Ryanodine 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 apparently gates the ryanodine receptor, opening and closing Ca 2+ channels  Many details are yet to be elucidated!

66 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

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

68 The Answers! 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

69 68 Transverse tubules connect plasma membrane of muscle cell to SR

70 69 Ca 2+ release during Excitation-Contraction coupling Ryanodyne R Ca-release ch.  Action potential on motor endplate travels down T tubules

71 70  Voltage -gated Ca 2+ channels open, Ca 2+ flows out SR into cytoplasm  Ca 2+ channels close when action potential ends. Active transport pumps continually return Ca 2+ to SR Ca ATPase (SERCA)

72 71 Excitation-Contraction Coupling  Depolarization of motor end plate (excitation) is coupled to muscular contraction  Nerve impulse travels along sarcolemma and down T-tubules to cause a release of Ca 2+ from SR  Ca 2+ binds to troponin and causes position change in tropomyosin, exposing active sites on actin  Permits strong binding state between actin and myosin and contraction occurs  ATP is hydrolyzed and energy goes to myosin head which releases from actin

73 72 Summary: Excitation-Contraction Coupling

74 IV Factors that Affect the Efficiency of Muscle Contraction

75 74 Tension and Load  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.

76 75 Preload  Preload is a load on the muscle before muscle contraction.  Determines the initial length of the muscle before contraction.  Initial length is the length of the muscle fiber before its contraction.  It is positively proportional to the preload.

77 76 The Effect of Sarcomere Length on Tension The Length – Tension Curve Concept of optimal length

78 77 Types of Contractions I  Twitch: a brief mechanical contraction of a single fiber produced by a single action potential at low frequency stimulation is known as single twitch.  Tetanus: It means a summation of twitches that occurs at high frequency stimulation

79 78 Effects of Repeated Stimulations Figure 10.15

80 79 1/sec5/sec10/sec50/sec

81 80 Afterload  Afterload is a load on the muscle after the beginning of muscle contraction.  The reverse force that oppose the contractile force caused by muscle contraction.  The afterload does not change the initial length of the muscle,  But it can prevent muscle from shortening because a part of force developed by contraction is used to overcome the afterload.

82 81  Afterload on muscle is resistance  Isometric  Length of muscle remains constant. Peak tension produced. Does not involve movement  Isotonic  Length of muscle changes. Tension fairly constant. Involves movement at joints  Resistance and speed of contraction inversely related Types of Contractions (II)

83 82 Isotonic and Isometric Contractions

84 83 Resistance and Speed of Contraction

85 84

86 85 Muscle Power Maximal power occurs where the product of force (P) and velocity (V) is greatest (P=FV) X Max Power= 4.5units

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