Chapter 9 Motor System - 1

Muscle Contraction and Motor Unit

Content

• Skeletal Muscle Contraction

• Motor Unit

Reference – Text Book

P160-163 P56 – 70P464

P85 – 91P673 - 674

Section I Skeletal Muscle Contraction

• Signal Transmission Through Neuromuscular Junction

• Molecular Mechanism of Muscle Contraction• Factors that Affect the Efficiency of Muscle

Contraction

Part I Signal Transmission Through the

Neuromuscular Junction

9

Skeletal Muscle Innervation

10

Illustration of the Neuromuscular Junction (NMJ)

11

New Ion Channel PlayersVoltage-gated Ca2+ channel

in presynaptic nerve terminalmediates neurotransmitter release

Nicotinic Acetylcholine Receptor Channelin muscle neuromuscular junction

(postsynaptic membrane, or end plate)mediates electrical transmission from nerve to

muscle

12

Neuromuscular Transmission

Skeletal Muscle

MyelinAxon

Axon Terminal

13

NeuromuscularNeuromuscular Transmission:Transmission:

Step by StepStep by StepNerve actionpotential invadesaxon terminal

-

+-

-

-

-

--

+

+

+

+

+

++

--

-

++

Depolarizationof terminalopens Ca channels

Lookhere

+ +

14K+

Outside

Inside

Na+

Na+

Na+Na+

Na+

Na+

Na+ Na+Na+

Na+

Na+

Na+

K+ K+

K+

K+

K+

K+

K+K+

K+

K+ K+

ACh

ACh

ACh

Ca2+ induces fusion ofvesicles with nerveterminal membrane.

ACh is released anddiffuses acrosssynaptic cleft.

ACh

ACh binds to itsreceptor on thepostsynaptic membrane

Binding of ACh openschannel pore that ispermeable to Na+ and K+.

Na+

Na+

K+

Muscle membrane

Nerveterminal

Ca2+

Ca2+

15

End Plate Potential (EPP ，终板电位 )

Outside

Inside

Muscle membrane

Presynapticterminal M

uscl

e M

embr

ane

Volta

ge (m

V)Time (msec)

-90 mV

VK

VNa

0

Threshold

Presynaptic AP

EPP

The movement of Na+ and K+

depolarizes muscle membranepotential (EPP)

ACh Receptor Channels Voltage-gatedNa Channels Inward Rectifier

K Channels

16

Meanwhile ...

Outside

Inside

ACh

ACh unbinds fromits receptor

Muscle membrane

ACh

so the channel closes

ACh

AChNerveterminal

ACh is hydrolyzed byAChE into Cholineand acetateCholine

Acetate

Choline is taken upinto nerve terminal

Choline

Choline resynthesizedinto ACh and repackagedinto vesicle

ACh

17

Structural Reality

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

19

Clinical ChemistryAch is the naturalagonist at the neuromuscularjunction.

Tubocurarine is theprimary paralyticingredient in curare.

Tubocurarine competeswith ACh for bindingto receptor- but doesnot open the pore.

So tubocurarine is aneuromuscularblocking agent.

Tubocurarine and other,related compoundsare used to paralyzemuscles during surgery.

Carbachol is asynthetic agonistnot hydrolyzed byacetylcholinesterase.

Carbachol and relatedcompounds are usedclinically for GI disorders,glaucoma, salivarygland malfunction, etc.

Suberyldicholine is asynthetic neuromuscularagonist.

Related compounds areuseful in the neuroscienceresearch

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

21

1. Normal:

ACh Choline + Acetate AChE

2. With anti - AchE:

ACh Choline + Acetate anti - AChE

Anticholinesterase Agents

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 ))

23

NMJ DiseasesMyasthenia Gravis （重症肌无力）

Autoimmunity to ACh receptorFewer functional ACh receptorsLow “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 ＋

channelsReduced ACh releaseLow “safety factor” for NM transmission

Prat II Molecular Mechanism of Muscle Contraction

25

Structure of Skeletal Muscle:Microstructure

Sarcolemma （肌管系统）Transverse (T) tubuleLongitudinal 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)

26

Within the Sarcoplasm

Transverse tubules （横管） Sarcoplasmic reticulum - Storage sites for calcium

Terminal cisternae - Storage sites for calcium

Triad （三联管）

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

28

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)

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

31

The Sliding Filament Model of Muscle Contraction

32

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

33

Energy for Muscle Contraction

ATP is required for muscle contractionMyosin ATPase breaks down ATP as fiber

contracts

34

Nerve Activation of Individual Muscle Cells (cont.)

35

Action potential along T-tubule causes release of calcium from cisternae of TRIAD

Cross-bridge cycle

Excitation/contraction coupling

Begin cycle with myosin already bound to actin

37

1. Myosin heads form cross bridges

Myosin head is tightly bound to actin in rigor state

Nothing bound to nucleotide binding site

38

2. ATP binds to myosin

Myosin changes conformation, releases actin

39

3. ATP hydrolysis

ATP is broken down into:ADP + Pi

(inorganic phosphate)

Both ADP and Pi remain bound to myosin

40

4. Myosin head changes conformation

Myosin head rotates and binds to new actin molecule

Myosin is in high energy configuration

41

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.

42

6. Release of ADP

Myosin head is again tightly bound to actin in rigor state

Ready to repeat cycle

43

THE CROSS-BRIDGE CYCLE

ATPADP + Pi

AM

A – M ATP AMADPPi

A + M ADP Pi

Relaxed state

Crossbridge energised

Crossbridge attachment

Tension develops

Crossbridge detachment

Ca2+ present

A, Actin; M, Myosin

44

Cross Bridge Cycle

45

Rigor mortis

Myosin cannot release actin until a new ATP molecule binds

Run out of ATP at death, cross-bridges never release

46

Many contractile cycles occur asynchronously during a single

muscle contraction

• Need steady supply of ATP!

47

Regulation of Contraction

Tropomyosin blocks myosin binding in absence of Ca2+

Low intracellular Ca2+

when muscle is relaxed

48

Ca+2 binds to troponin during

contraction Troponin-Ca2+

pulls tropomyosin, unblocking myosin-binding sites

Myosin-actin cross-bridge cycle can now occur

49

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

50

Ca2+ Controls Contraction

Ca2+ Channels and Pumps

Release of Ca2+ from

the SR triggers

contraction

Reuptake of Ca2+ into

SR relaxes muscle

Structures involved in EC coupling- Skeletal Muscle -

Structures involved in EC coupling- Skeletal Muscle -

outin

voltage sensor? junction foot

sarcoplasmic reticulum

sarcolemmaT-tubule

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 Ca2+ channel

In skeletal muscle, voltage-sensing protein undergoes voltage-dependent conformational

changes

53

Ryanodine ( 利阿诺定 ) Receptor

The "foot structure" in terminal cisternae of SR Foot structure is 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!

outin

voltage sensor(DHP receptor) junctional foot

(ryanodine receptor)

sarcoplasmic reticulum

sarcolemmaT-tubule

Skeletal muscleSkeletal 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

Cardiac muscleCardiac muscle The AP:

moves down the t-tubule

voltage change detected by DHP receptors (Ca2+ channels) which 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!

outin

voltage sensor& Ca channel

(DHP receptor)

junctional foot(ryanodine receptor)

sarcoplasmic reticulum

sarcolemmaT-tubule

ComparisonComparisonSkeletal

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

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

57

Summary: Excitation-Contraction Coupling

Part III Factors that Affect the Efficiency of Muscle Contraction

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.

60

Preload 前负荷Preload

load on the muscle before muscle contraction. Determines the initial length of the muscle

before contraction.

Initial lengththe length of the muscle fiber before its

contraction. positively proportional to the preload.

61

The Effect of Sarcomere Length on Tension

The Length – Tension CurveConcept of optimal length

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

63

Effects of Repeated Stimulations

Figure 10.15

64

1/sec 5/sec 10/sec 50/sec

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

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)

67

Isotonic and Isometric Contractions

68

Resistance and Speed of Contraction

69

70

Muscle PowerMuscle PowerMaximal power occurs where the product of

force (P) and velocity (V) is greatest (P=FV)

X Max Power= 4.5units

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

Extrafusal Muscle: innervated by Alpha motor neuron

Intrafusal muscle: innervated by Gamma motor neurons

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）

•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

Overview - organization of motor systems

Motor CortexMotor Cortex

Brain StemBrain Stem

Spinal CordSpinal Cord

Skeletal muscle

-motor neuron

Final common pathway

Final common path - -motor neuron

(-)

musclefibers

(+)

(-)

(+)

axon hillock

motor nerve fiber

NM junction

Schwanncells

Receptors? acetylcholineesterase

Transmitter?

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