Transcript section 3 2011 muscle contraction

LIU Chuan Yong
刘传勇
Institute of Physiology
Medical School of SDU
Tel 88381175 (lab)
88382098 (office)
Email: [email protected]
Website: www.physiology.sdu.edu.cn
1
Section 3
Muscle Contraction
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
3
Skeletal Muscle
Cardiac Muscle
Smooth Muscle
4
I Signal Transmission Through
the Neuromuscular Junction
Skeletal Muscle Innervation
6
Illustration of the Neuromuscular
Junction (NMJ)
7
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
8
Nerve Terminal
2+
Ca
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
9
Neuromuscular Transmission
Axon
Axon Terminal
Skeletal Muscle
10
Depolarization
Nerve
action
of terminal
opens Cainvades
channels +
potential
+
axon terminal
-
-
-
-
Neuromuscular
Transmission:
+
Step by Step
-
+
+
+
Look - +
here + -
-+
+
-++
-
11
Binding
ACh
ACh
of
is ACh
released
to its
opens
andof
2+binds
Ca
induces
fusion
channel
receptor
diffuses
pore
on
across
that
thenerve
is
vesicles
with
+ and K+.
permeable
postsynaptic
synaptic
to
cleft.
Na
membrane
terminal membrane.
ACh ACh
ACh
Ca2+
Ca2+
Na+
Na+
Na+
K+
Na+
K+
Na+
K+
ACh
Na+
Na+
K+
Na+
Na+
K+
Outside
Muscle membrane
Na+
K+
Na+
K+
Na+
K+
Inside
K+
Na+
K+
K+
K+
K+
Na+
12
End Plate Potential (EPP)
Presynaptic
terminal
VNa
Muscle Membrane
Voltage (mV)
The movement of Na+ and K+
depolarizes muscle membrane
potential (EPP)
0
EPP
Threshold
-90 mV
VK
Presynaptic
AP
Time (msec)
Outside
Muscle membrane
Inside
ACh Receptor Channels
Voltage-gated
Na Channels
Inward Rectifier
K Channels
13
ACh
Choline
ACh ACh
Choline
Meanwhile ...
ACh
isthe
by
Choline
Choline
ishydrolyzed
taken
upfrom
ACh
unbinds
soresynthesized
channel
closes
AChE
into
Choline
into
ACh
and
repackaged
into
nerve
terminal
its
receptor
acetate
into and
vesicle
ACh
Acetate
ACh
Outside
Muscle membrane
Inside
14
Structural Reality
15
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
16
Ach is the natural
agonist at the
neuromuscular
junction.
Carbachol and related
compounds are used
Carbachol
is disorders,
a
clinically
for GI
synthetic
agonist
glaucoma,
salivary
notmalfunction,
hydrolyzed etc.
by
gland
acetylcholinesterase.
Related
compounds
Suberyldicholine
is are
a
useful
in the
neuroscience
synthetic
neuromuscular
research
agonist.
Clinical Chemistry
Tubocurarine
other,
Tubocurarineand
competes
SoTubocurarine
tubocurarine
a
related
compounds
with
ACh
for binding
isisthe
neuromuscular
are
used
to paralyze
to
receptorbut does
primary
paralytic
blocking
agent.
muscles
not
openduring
the
pore.
ingredient
insurgery.
curare.
17
Anticholinesterase Agents
Anticholinesterase (anti-ChE) agents
inhibit acetylcholinesterase （乙酰胆碱酯
酶）
prolong excitation at the NMJ
18
Anticholinesterase Agents
1. Normal:
ACh
Choline + Acetate
AChE
2. With anti - AchE:
ACh
Choline + Acetate
anti - AChE
19
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))
20
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.
21
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
Low “safety factor” for NM transmission
22
II Microstructure of
Skeletal Muscle
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
24
 Fascicles: bundles, CT(connective tissue) covering on
each one
 Muscle fibers: muscle cells
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)
26
Within the sarcoplasm
Triad （三
联管）
 Transverse tubules
 Sarcoplasmic reticulum -Storage sites for calcium
 Terminal cisternae - Storage sites for calcium
27
Microstructure of Skeletal
Muscle (myofibril)
28
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
29
30
Myosin head is hinged Myosin 肌球蛋白
Bends and straightens during contraction
31
Thick filaments (myosin)
Bundle of myosin proteins shaped like doubleheaded 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
32
Thin filaments
原肌球蛋白
肌钙蛋白
肌动蛋白
33
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+
34
 Thick filament: Myosin (head and tail)
 Thin filament: Actin, Tropomyosin, Troponin
(calcium binding site)
35
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
36
The Sliding Filament Model of Muscle Contraction
37
Changes in the appearance of a Sarcomere during
the Contraction of a Skeletal Muscle Fiber
38
Cross-Bridge Formation in
Muscle Contraction
39
Energy for Muscle Contraction
ATP is required for muscle contraction
Myosin ATPase breaks down ATP as fiber
contracts
40
Nerve Activation of Individual
Muscle Cells (cont.)
41
Excitation/contraction coupling
 Action potential along T-tubule causes release
of calcium from cisternae of TRIAD
 Cross-bridge cycle
42
Begin cycle with myosin
already bound to actin
1. Myosin heads form cross bridges
 Myosin head is
tightly bound to
actin in rigor state
 Nothing bound to
nucleotide binding
site
44
2. ATP binds to myosin
Myosin
changes
conformation,
releases actin
45
3. ATP hydrolysis
ATP is broken
down into:
ADP + Pi
(inorganic
phosphate)
Both ADP and Pi
remain bound to
myosin
46
4. Myosin head changes
conformation
 Myosin head
rotates and
binds to new
actin
molecule
 Myosin is in
high energy
configuration
47
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.
48
6. Release of ADP
 Myosin head is
again tightly
bound to actin
in rigor state
 Ready to repeat
cycle
49
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
Al M
A, Actin; M, Myosin
50
Cross Bridge Cycle
51
Rigor mortis
 Myosin cannot release actin until a new
ATP molecule binds
 Run out of ATP at death, cross-bridges
never release
52
Many contractile cycles occur
asynchronously during a single
muscle contraction
• Need steady supply of ATP!
53
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?
Regulation of Contraction
 Tropomyosin
blocks myosin
binding in
absence of Ca2+
 Low intracellular
Ca2+ when muscle
is relaxed
55
2+
Ca binds
to troponin during
contraction
 Troponin-Ca+2
pulls tropomyosin,
unblocking
myosin-binding
sites
 Myosin-actin
cross-bridge cycle
can now occur
56
How does
2+
Ca
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
57
Ca2+ Controls Contraction
Ca2+ Channels and Pumps
 Release of Ca2+ from the SR triggers
contraction
 Reuptake of Ca2+ into SR relaxes muscle
58
59
Structures involved in EC coupling
- Skeletal Muscle T-tubule
sarcolemma
voltage sensor?
out
in
sarcoplasmic
reticulum
junction foot
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
61
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!
62
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
T-tubule
sarcolemma out
in sarcoplasmic
reticulum
voltage sensor
(DHP receptor)
junctional foot
(ryanodine receptor)
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!
T-tubule
sarcolemma out
in sarcoplasmic
reticulum
voltage sensor
junctional foot
& Ca channel
(DHP receptor) (ryanodine receptor)
The Answers!
Skeletal
Cardiac
 The trigger for SR release  The trigger for SR release
appears to be calcium
appears to be voltage
(Calcium Activated
(Voltage Activated Calcium
Calcium Release - CACR)
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
 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
Transverse tubules connect plasma
membrane of muscle cell to SR
66
Ca2+ release during Excitation-Contraction coupling
 Action
potential on
motor
endplate
travels
down T
tubules
Ryanodyne R
Ca-release ch.
67
 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)
68
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
69
Summary: Excitation-Contraction Coupling
70
IV Factors that Affect the
Efficiency of Muscle
Contraction
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.
72
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.
73
The Effect of Sarcomere Length on Tension
The Length – Tension Curve
Concept of optimal length
74
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
75
Effects of Repeated Stimulations
Figure76
10.15
1/sec
5/sec
10/sec
50/sec
77
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
78
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
79
Isotonic and Isometric Contractions
80
Resistance and Speed of Contraction
81
82
Muscle Power
Maximal power occurs where the product of
force (P) and velocity (V) is greatest (P = FV)
X
Max Power=
4.5units
83