11

LIU Chuan Yong

刘传勇

Institute of Physiology

Medical School of SDU

Tel 88381175 (lab)

88382098 (office)

Email: liucy@sdu.edu.cn

Website: www.physiology.sdu.edu.cn

Section 4

Muscle ContractionMuscle Contraction

33

Classification of the MuscleClassification 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

44

Skeletal Muscle Cardiac Muscle

Smooth Muscle

I Signal Transmission Through the Neuromuscular Junction

66

Skeletal Muscle Innervation

77

Illustration of the Neuromuscular Junction (NMJ)

88

New Ion Channel Players

Voltage-gated Ca2+ channelin presynaptic nerve terminalmediates neurotransmitter release

Nicotinic Acetylcholine Receptor Channelin muscle neuromuscular junction (postsynaptic

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

muscle

99

Nerve Terminal Ca2+ channels

Structurally similar to Na+ channelsFunctionally similar to Na+ channels

exceptactivation occurs at more positive potentialsactivation and inactivation much slower than

Na+ channels

1010

Neuromuscular Transmission

Skeletal Muscle

MyelinAxon

Axon Terminal

1111

NeuromuscularNeuromuscular Transmission:Transmission:

Step by StepStep by StepNerve actionpotential invadesaxon terminal

-

+-

-

-

-

--

+

+

+

+

+

++

--

-

+ +

Depolarizationof terminalopens Ca channels

Lookhere

+ +

1212K+

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+

1313

End Plate Potential (EPP)

Outside

Inside

Muscle membrane

Presynapticterminal M

usc

le M

em

bra

ne

Vo

ltage

(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

1414

Meanwhile ...

Outside

Inside

ACh

ACh unbinds fromits receptor

Muscle membrane

ACh

so the channel closes

ACh

AChNerveterminal

ACh is hydrolyzed byAChE into Cholineand acetate

Choline

Acetate

Choline is taken upinto nerve terminal

Choline

Choline resynthesizedinto ACh and repackagedinto vesicle

ACh

1515

Structural Reality

1616

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

1717

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

1818

Anticholinesterase Agents

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

1919

1. Normal:

ACh Choline + Acetate AChE

2. With anti - AchE:

ACh Choline + Acetate anti - AChE

Anticholinesterase Agents

2020

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 ))

2121

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.

2222

SarinSarin

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.

2323

NMJ Diseases

Myasthenia 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 ＋ ch

annelsReduced ACh releaseLow “safety factor” for NM transmission

II Microstructure of Skeletal Muscle

2525

Skeletal Muscle

Human body contains over 400 skeletal muscles40-50% of total body weight

Functions of skeletal muscleForce production for locomotion and

breathingForce production for postural supportHeat production during cold stress

2626

Fascicles: bundles, CT(connective tissue) covering on each one

Muscle fibers: muscle cells

2727

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)

2828

Within the sarcoplasm

Transverse tubules

Sarcoplasmic reticulum -Storage sites for calcium

Terminal cisternae - Storage sites for calcium

Triad （三联管）

2929

Microstructure of Skeletal Muscle (myofibril)

3030

Sarcomeres Sarcomere 肌小节 : bundle of alternating thi

ck 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

3131

3232

Myosin head is hinged Bends and straightens during contraction

Myosin 肌球蛋白

3333

Thick filaments (myosin)Bundle of myosin proteins shaped like double-heade

d golf clubsMyosin heads have two binding sites

Actin binding site forms cross bridgeNucleotide binding site binds ATP (Myosin ATPase)

Hydrolysis of ATP provides energy to generate power stroke

3434

Thin filaments

原肌球蛋白 肌钙蛋白

肌动蛋白

3535

Thin filaments (actin)Backbone: two strands of polymerized globular acti

n – fibrous actinEach actin has myosin binding site

TroponinBinds Ca2+; regulates muscle contraction

TropomyosinLies in groove of actin helixBlocks myosin binding sites in absence of Ca2+

3636

Thick filament: Myosin (head and tail) Thin filament: Actin, Tropomyosin, Troponin (calci

um binding site)

3737

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

3838

The Sliding Filament Model of Muscle Contraction

3939

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

4040

Cross-Bridge Formation in Muscle Contraction

4141

Energy for Muscle Contraction

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

contracts

4242

Nerve Activation of Individual Muscle Cells (cont.)

4343

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

Cross-bridge cycle

Excitation/contraction coupling

Begin cycle with myosin alreBegin cycle with myosin already bound to actinady bound to actin

4545

1. Myosin heads form cross bridges1. Myosin heads form cross bridges

Myosin head is tightly bound to actin in rigor state

Nothing bound to nucleotide binding site

4646

2. ATP binds to myosin2. ATP binds to myosin

Myosin changes conformation, releases actin

4747

3. ATP hydrolysis3. ATP hydrolysisATP is broken

down into:ADP + Pi

(inorganic phosphate)

Both ADP and Pi remain bound to myosin

4848

4. Myosin head changes 4. Myosin head changes conformationconformation

Myosin head rotates and binds to new actin molecule

Myosin is in high energy configuration

4949

5. Power stroke5. Power stroke Release of Pi from myo

sin 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.

5050

6. Release of ADP6. Release of ADP

Myosin head is again tightly bound to actin in rigor state

Ready to repeat cycle

5151

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

5252

Cross Bridge Cycle

5353

Rigor mortis Rigor mortis

Myosin cannot release actin until a new ATP molecule binds

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

5454

Many contractile cycles Many contractile cycles occur occur asynchronously during a single asynchronously during a single

muscle contractionmuscle contraction

• Need steady supply of ATP!

5555

Regulation of ContractionRegulation of Contraction

Tropomyosin blocks myosin binding in absence of Ca2

+

Low intracellular Ca2+

when muscle is relaxed

5656

CaCa+2+2 binds to troponin during contbinds to troponin during cont

ractionraction Troponin-Ca+2 pul

ls tropomyosin, unblocking myosin-binding sites

Myosin-actin cross-bridge cycle can now occur

5757

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 cyto

plasm

The action potential triggers The action potential triggers contractioncontraction

The action potential triggers The action potential triggers contractioncontraction

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?

Z disc

A band(myosin)

I band(actin)

Z disc M line Z disc

sarcoplasmicreticulum

t-tubules

junctional feetTriad

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

Structures involved in EC coupling

Structures involved in EC couplingStructures involved in EC coupling- - Skeletal Muscle -Skeletal Muscle -

Structures involved in EC couplingStructures involved in EC coupling- - Skeletal Muscle -Skeletal Muscle -

outin

voltage sensor? junction foot

sarcoplasmic reticulum

sarcolemmaT-tubule

6161

CaCa2+2+ Controls Contraction Controls Contraction

Ca2+ Channels and Pumps Release of Ca2+ from the SR triggers

contraction Reuptake of Ca2+ into SR relaxes muscle So how is calcium released in response

to nerve impulses? Answer has come from studies of

antagonist molecules that block Ca2+ channel activity

6262

6363

Dihydropyridine ReceptorDihydropyridine 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 Ca2+

channel In skeletal muscle, DHP receptor is apparently

a voltage-sensing protein and probably undergoes voltage-dependent conformational changes

6464

Ryanodine ReceptorRyanodine 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 apparently 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 muscleSkeletal 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 muscleCardiac muscleCardiac 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!

outin

voltage sensor& Ca channel

(DHP receptor)

junctional foot(ryanodine receptor)

sarcoplasmic reticulum

sarcolemmaT-tubule

The Answers!The Answers!The Answers!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

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

6868

Transverse tubules connect plasma membrane of muscle cell to SR

6969

Ca2+ release during Excitation-Contraction coupling

Ryanodyne RCa-release ch.

Action potential on motor endplate travels down T tubules

7070

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)

7171

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

7272

Summary: Excitation-Contraction CouplingSummary: Excitation-Contraction Coupling

IV Factors that Affect the Efficiency of Muscle

Contraction

7474

Tension and Load The force exerted on an object by a contr

acting muscle is known as tension. The force exerted on the muscle by an ob

ject (usually its weight) is termed load. According to the time of effect exerted b

y the loads on the muscle contraction the load was divided into two forms, preload and afterload.

7575

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.

7676

The Effect of Sarcomere Length on Tension

The Length – Tension Curve

Concept of optimal length

7777

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

7878

Effects of Repeated Stimulations

Figure 10.15

7979

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

8080

AfterloadAfterload

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.

8181

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)

8282

Isotonic and Isometric Contractions

8383

Resistance and Speed of Contraction

8484

8585

Muscle PowerMuscle PowerMaximal power occurs where the product of

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

X Max Power= 4.5units