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

2. Section 3
Muscle Contraction

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

4. Skeletal Muscle
Cardiac Muscle
Smooth Muscle

5. I Signal Transmission Through the Neuromuscular Junction

6. Skeletal Muscle Innervation

7. Illustration of the Neuromuscular Junction (NMJ)

8. New Ion Channel Players
Voltage-gated Ca2+ 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

9. Nerve Terminal Ca2+ 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

10. Neuromuscular Transmission
Myelin
Axon
Axon Terminal
Skeletal Muscle

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

12. postsynaptic membrane ACh is released and diffuses across
Binding of ACh opens
channel pore that is
permeable to Na+ and K+.
ACh binds to its
receptor on the
postsynaptic membrane
ACh is released and
diffuses across
synaptic cleft.
Ca2+ induces fusion of
vesicles with nerve
terminal membrane.
ACh
ACh
ACh
Nerve
terminal
Ca2+
Ca2+
Na+
Na+
Na+
Na+ K+
Na+ K+
Na+ K+ K+
ACh
Na+
Na+
Na+ K+
Outside
Muscle membrane
Na+
Na+
Inside K+ K+
Na+ K+ K+ K+ K+ K+
Na+ K+
Na+

13. End Plate Potential (EPP)
The movement of Na+ and K+
depolarizes muscle membrane
potential (EPP)
VNa
EPP
Muscle Membrane
Voltage (mV)
Threshold
Presynaptic
terminal
-90 mV VK
Time (msec)
Presynaptic AP
Outside
Muscle membrane
Inside
Voltage-gated
Na Channels
ACh Receptor Channels
Inward Rectifier
K Channels

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

15. Structural Reality

16. Neuromuscular Transmission
Properties of neuromuscular junction
1:1 transmission
An unidirectional process
Time delay. 20nm/0.5-1ms
Easily affect by drugs and some factors
The NMJ is a site of considerable clinical importance

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

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

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

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))

21. Sarin comes in both liquid and gas forms,
a highly toxic and volatile nerve agent developed by Nazi scientists in Germany in the 1930s.
500 times more toxic than cyanide （氢化物） gas.

22. 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 Ca2＋ channels
Reduced ACh release

23. II Microstructure of Skeletal Muscle

24. 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

25. Fascicles: bundles, CT(connective tissue) covering on each one
Muscle fibers: muscle cells

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

28. Microstructure of Skeletal Muscle (myofibril)

29. 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

31. Myosin 肌球蛋白 Myosin head is hinged
Bends and straightens during contraction

32. 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

33. Thin filaments
原肌球蛋白
肌钙蛋白
肌动蛋白

34. Thin filaments (actin)
Backbone: two strands of polymerized globular actin – fibrous actin
Each actin has myosin binding site
Troponin
Binds Ca2+; regulates muscle contraction
Tropomyosin
Lies in groove of actin helix
Blocks myosin binding
sites in absence of Ca2+

35. Thick filament: Myosin (head and tail)
Thin filament: Actin, Tropomyosin, Troponin (calcium binding site)

36. 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

37. The Sliding Filament Model of Muscle Contraction

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

39. Cross-Bridge Formation in Muscle Contraction

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

41. Nerve Activation of Individual Muscle Cells (cont.)

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

43. Begin cycle with myosin already bound to actin

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

45. 2. ATP binds to myosin
Myosin changes conformation, releases actin

46. 3. ATP hydrolysis ATP is broken down into:
ADP + Pi (inorganic phosphate)
Both ADP and Pi remain bound to myosin

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

48. 5. Power stroke
Release of Pi 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.

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

50. THE CROSS-BRIDGE CYCLE Relaxed state
Crossbridge energised
Crossbridge attachment
A + M l ADP l Pi
Ca2+ present
A – M l ATP
AlMlADPlPi
Crossbridge detachment
Tension develops
ADP + Pi
ATP
AlM
A, Actin; M, Myosin

51. Cross Bridge Cycle

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

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

54. The action potential triggers contraction
How does the AP trigger contraction?
We should ask:
how does the AP cause release of Ca2+ from the SR, so leading to an increase in [Ca2+]i?
how does an increase in [Ca2+]i cause contraction?

55. Regulation of Contraction
Tropomyosin blocks myosin binding in absence of Ca2+
Low intracellular Ca2+ when muscle is relaxed

56. Ca2+ binds to troponin during contraction
Troponin-Ca+2 pulls tropomyosin, unblocking myosin-binding sites
Myosin-actin cross-bridge cycle can now occur

57. How does Ca2+ get into cell?
Action potential releases intracellular Ca2+ from sarcoplasmic reticulum (SR)
SR is modified endoplasmic reticulum
Membrane contains Ca2+ pumps to actively transport Ca2+ into SR
Maintains high Ca2+ in SR, low Ca2+ in cytoplasm

58. Ca2+ Controls Contraction
Ca2+ Channels and Pumps
Release of Ca2+ from the SR triggers contraction
Reuptake of Ca2+ into SR relaxes muscle 19

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

61. 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 Ca2+ channel
In skeletal muscle
voltage-sensing protein
undergoes voltage-dependent conformational changes 20

62. Ryanodine (利阿诺定 ) Receptor
The "foot structure" in terminal cisternae of SR
a Ca2+ channel of unusual design
Conformation change or Ca2+ -channel activity of DHP receptor
gates the ryanodine receptor,
opening and closing Ca2+ channels
Many details are yet to be elucidated! 21

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

64. Cardiac muscle The AP: moves down the t-tubule
voltage change detected by DHP receptors (Ca2+ channels)
opens to allow small amount of (trigger) Ca2+ into the fibre
Ca2+ binds to ryanodine receptors which open to release a large amount of (activator) Ca2+ (CACR)
Thus, calcium, not voltage, appears to trigger Ca2+ release in Cardiac muscle!
out in
voltage sensor
& Ca channel
(DHP receptor)
junctional foot
(ryanodine receptor)
sarcoplasmic
reticulum
sarcolemma
T-tubule

65. The Answers! Skeletal Cardiac
The trigger for SR release appears to be calcium (Calcium Activated Calcium Release - CACR)
The t-tubule membrane has a Ca2+ channel (DHP receptor)
The ryanodine receptor is the SR Ca release channel
The ryanodine receptor is Ca-gated & Ca release is proportional to Ca2+ entry
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
Ca2+ release is proportional to membrane voltage

66. Transverse tubules connect plasma membrane of muscle cell to SR

67. Ca2+ release during Excitation-Contraction coupling
Action potential on motor endplate travels down T tubules
Ryanodyne R
Ca-release ch.

68. Voltage -gated Ca2+ channels open, Ca2+ flows out SR into cytoplasm
Ca2+ channels close when action potential ends. Active transport pumps continually return Ca2+ to SR
Ca ATPase
(SERCA)

69. 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 Ca2+ from SR
Ca2+ 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

70. Summary: Excitation-Contraction Coupling

71. IV Factors that Affect the Efficiency of Muscle Contraction

72. 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.

73. 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.

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

75. 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

76. Effects of Repeated Stimulations
Figure 10.15

77. 1/sec
5/sec
10/sec
50/sec

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

79. Types of Contractions (II)
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

80. Isotonic and Isometric Contractions

81. Resistance and Speed of Contraction

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