(and contraction).

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Skeletal Muscle
骨骼肌
Qiang XIA (夏强), PhD
Department of Physiology
Room C518, Block C, Research Building, School of Medicine
Tel: 88206417, 88208252
Email: xiaqiang@zju.edu.cn
Muscle
Types of muscle:

Skeletal muscle骨骼肌

Cardiac muscle 心肌

Smooth muscle平滑肌
Striated muscle
横纹肌
Muscle (cont.)
• The sliding filament mechanism(肌丝滑行机制), in which
myosin(肌凝蛋白) filaments bind to and move actin (肌纤
蛋白)filaments, is the basis for shortening of stimulated
skeletal, smooth, and cardiac muscles.
• In all three types of muscle, myosin and actin interactions are
regulated by the availability of calcium ions.
• Changes in the membrane potential of muscles are linked
to internal changes in calcium release (and contraction).
Muscle (cont.)
• Neuronal influences on the contraction of muscles is
affected when neural activity causes changes in the
membrane potential of muscles.
• Smooth muscles operate in a wide variety of involuntary
functions such as regulation of blood pressure and
movement of materials in the gut.
Structure of skeletal muscle
Skeletal muscles
are attached to the
skeleton by tendons.
Skeletal muscles typically contain
many, many muscle fibers.
The sarcomere(肌小节) is composed of:
thick filaments called myosin, anchored
in place by titin fibers, and
thin filaments called actin, anchored to
Z-lines .
A cross section through a sarcomere shows that:
• each myosin can interact with 6 actin filaments, and
• each actin can interact with 3 myosin filaments.
Sarcomere structures in an electron micrograph.
Filaments
Myosin filament (thick filament)粗肌丝

Myosin肌凝蛋白
Actin filament (thin filament)细肌丝



Actin肌纤蛋白
Tropomyosin原肌凝蛋白
Troponin肌钙蛋白
Titin肌联蛋白
Sarcotubular system
(1) Transverse Tubule横管
(2) Longitudinal Tubule纵管
Sarcoplasmic reticulum肌浆网
Molecular mechanisms of contraction
Sliding-filament mechanism
Contraction
(shortening):
myosin binds to
actin, and slides
it, pulling the
Z-lines closer
together, and
reducing the
width of the
I-bands.
Note that filament
lengths have not
changed.
Contraction:
myosin’s cross-bridges(横桥) bind to actin;
the crossbridges then flex to slide actin.
Click here to play the
Sarcomere Shortening
Flash Animation
The thick filament called myosin is actually a
polymer of myosin molecules, each of which
has a flexible cross-bridge that binds ATP and actin.
The cross-bridge cycle
requires ATP
1. The myosin-binding site on actin
becomes available, so the
energized cross-bridge binds.
2.
4. Partial
hydrolysis of
the bound ATP
energizes
or “re-cocks”
the bridge.
3.
The full
hydrolysis
and departure
of ADP + Pi
causes the
flexing of
the bound
cross-bridge.
Binding of a “new” ATP
to the cross-bridge
uncouples the bridge.
1. The myosin-binding site on actin
becomes available, so the
energized cross-bridge binds.
2.
The full
hydrolysis
and departure
of ADP + Pi
causes the
flexing of
the bound
cross-bridge.
3.
Binding of a “new” ATP
to the cross-bridge
uncouples the bridge.
4. Partial
hydrolysis of
the bound ATP
energizes
or “re-cocks”
the bridge.
The cross-bridge cycle
requires ATP
1. The myosin-binding site on actin
becomes available, so the
energized cross-bridge binds.
2.
4. Partial
hydrolysis of
the bound ATP
energizes
or “re-cocks”
the bridge.
3.
The full
hydrolysis
and departure
of ADP + Pi
causes the
flexing of
the bound
cross-bridge.
Binding of a “new” ATP
to the cross-bridge
uncouples the bridge.
Click here to play the
Cross-bridge cycle
Flash Animation
Roles of troponin,
tropomyosin, and
calcium in
contraction
In relaxed skeletal muscle, tropomyosin blocks
the cross-bridge binding site on actin.
Contraction occurs when calcium ions bind to
troponin; this complex then pulls tropomyosin
away from the cross-bridge binding site.
Interaction of myosin and actin
Excitation-contraction coupling
兴奋-收缩偶联

Transmission of action potential (AP)
along T tubules

Calcium release caused by T tubule AP

Contraction initiated by calcium ions
The latent period between excitation and development
of tension in a skeletal muscle includes the time
needed to release Ca++ from sarcoplasmic reticulum,
move tropomyosin, and cycle the cross-bridges.
The transverse tubules bring
action potentials into the
interior of the skeletal muscle
fibers, so that the wave of
depolarization passes close
to the sarcoplasmic reticulum,
stimulating the release of
calcium ions.
The extensive meshwork
of sarcoplasmic reticulum
assures that when it
releases calcium ions
they can readily diffuse
to all of the troponin sites.
Passage of an action
potential along the
transverse tubule opens
nearby voltage-gated
calcium channels, the
“ryanodine receptor,”
located on the
sarcoplasmic
reticulum, and
calcium ions released into the
cytosol bind to troponin.
The calcium-troponin
complex “pulls” tropomyosin
off the myosin-binding site of
actin, thus allowing the
binding of the cross-bridge,
followed by its flexing to
slide the actin filament.
 Which
of these following proteins contains
the binding sites for Ca2+ that initiates
contraction?
A Myosin
B Troponin I
C Tropomyosin
D Troponin C
E Troponin T
General process of excitation and
contraction in skeletal muscle

Neuromuscular transmission

Excitation-contraction coupling

Muscle contraction
A single motor unit(运动单位)
consists of a motor neuron and
all of the muscle fibers it
controls.
The neuromuscular junction(
神经肌接头)is the point of
synaptic contact between the
axon terminal of a motor
neuron and the muscle fiber it
controls.
Action potentials in the
motor neuron cause
Acetylcholine(乙酰胆碱)
release into the neuromuscular
junction.
Muscle contraction follows the delivery
of acetylcholine to the muscle fiber.
1. The exocytosis of acetylcholine from the axon terminal
occurs when the acetylcholine vesicles merge into the
membrane covering the terminal.
2. On the membrane of the muscle fiber, the receptors for
acetylcholine respond to its binding by increasing
Na+ entry into the fiber, causing a graded depolarization.
3. The graded depolarization typically exceeds threshold for
the nearby voltage-gate Na+ and K+ channels, so an
action potential occurs on the muscle fiber.
Nicotinic acetylcholine receptor
烟碱型乙酰胆碱受体
Acetylcholinesterase
乙酰胆碱酯酶
End plate potential (EPP)
终板电位
Miniature end plate potential
微终板电位


Small fluctuations (typically 0.5 mV) in the resting potential of
postsynaptic cells.
They are the same shape as, but much smaller than, the end plate
potentials caused by stimulation of the presynaptic cell. Miniature end
plate potentials are considered as evidence for the quantal release of
neurotransmitters at chemical synapses, a single miniature end plate
potential resulting from the release of the contents of a single synaptic
vesicle.
Click here to play the
Neuromuscular Junction
Flash Animation
Click here to play the
Action Potentials and
Muscle Contraction
Flash Animation

A woman comes to your clinic and explains that she is noting
gradually worsening fatigue/weakness in her legs when she goes
for her walk. She also mentions a droopy right eyelid, and wonders
if this is a normal aging process.You examine her and find the
following: overall decreased muscle strength, trace reflexes
throughout, and weakness of eyelid closure bilaterally.The rest of
the exam is unremarkable. What would you administer to treat
the likely condition?
A Muscarinic blockers
B Nicotinic blockers
C Acetylcholinesterase blockers
D Alpha blockers
E Beta blockers

A woman comes to your clinic and explains that she is noting
gradually worsening fatigue/weakness in her legs when she goes
for her walk. She also mentions a droopy right eyelid, and wonders
if this is a normal aging process.You examine her and find the
following: overall decreased muscle strength, trace reflexes
throughout, and weakness of eyelid closure bilaterally.The rest of
the exam is unremarkable. What would you administer to treat
the likely condition?
A Muscarinic blockers
B Nicotinic blockers
C Acetylcholinesterase blockers
D Alpha blockers
E Beta blockers

Neuromuscular transmission
A Is caused by the release of acetylcholine from
the muscle side of the junction
B Shows a permeability change to Na+ and K+ at
the receptor site during the endplate potential (EPP)
C May be facilitated by curare in myasthenia gravis
D Is blocked by curare because it competes with
the Na+ entry during the muscle action potential
E Is solely an electronic function

Neuromuscular transmission
A Is caused by the release of acetylcholine from
the muscle side of the junction
B Shows a permeability change to Na+ and K+ at
the receptor site during the endplate potential (EPP)
C May be facilitated by curare in myasthenia gravis
D Is blocked by curare because it competes with
the Na+ entry during the muscle action potential
E Is solely an electronic function

A miniature end-plate potential is
A Not related to changes in ionic permeability
B A reduced action potential in the motor endplate
C Produced by spontaneous release of
acetylcholine
D Responsible for weak muscular contractions
E An afterdischarge at the neuromuscular
junction

A miniature end-plate potential is
A Not related to changes in ionic permeability
B A reduced action potential in the motor endplate
C Produced by spontaneous release of
acetylcholine
D Responsible for weak muscular contractions
E An afterdischarge at the neuromuscular
junction

The action of acetylcholine at the neuromuscular
junction is terminated primarily by
A Enzymatic breakdown by choline acetylase
B Enzymatic breakdown by
acetylcholinesterase
C Uptake into the muscle
D Uptake into the nerve ending
E Diffusion into the surrounding extracellular
fluid

The action of acetylcholine at the neuromuscular
junction is terminated primarily by
A Enzymatic breakdown by choline acetylase
B Enzymatic breakdown by
acetylcholinesterase
C Uptake into the muscle
D Uptake into the nerve ending
E Diffusion into the surrounding extracellular
fluid
 The
transmission of an action potential over
the muscle fiber membrane causes the
contraction of the fiber a few milliseconds
later. Which of the following terms is used to
describe that process?
A Ratchet Theory of Muscle Contraction
B Excitation Contraction Coupling
C Membrane Potential
D All-or -Nothing Law
 The
transmission of an action potential over
the muscle fiber membrane causes the
contraction of the fiber a few milliseconds
later. Which of the following terms is used to
describe that process?
A Ratchet Theory of Muscle Contraction
B Excitation Contraction Coupling
C Membrane Potential
D All-or -Nothing Law
Mechanics of single-fiber contraction

Muscle tension 肌张力 – the force exerted on an object by a
contracting muscle

Load 负荷 – the force exerted on the muscle by an object
(usually its weight)

Isometric contraction 等长收缩 – a muscle develops tension but
does not shorten (or lengthen) (constant length)

Isotonic contraction 等张收缩 – the muscle shortens while the
load on the muscle remains constant (constant tension)
Twitch contraction 单收缩
 The
mechanical response of a single
muscle fiber to a single action potential is
know as a TWITCH
iso = same
tonic = tension
metric = length
Tension increases
rapidly and
dissipates slowly
Shortening occurs
slowly, only after
taking up elastic
tension; the
relaxing muscle
quickly returns to
its resting length.
All three are isotonic contractions.
1.
2.
3.
4.
Latent period潜伏期
Velocity of shortening
Duration of the twitch
Distance shortened
Load-velocity relation 长度-速度关系
Click here to play the
Mechanisms of
Single Fiber Contraction
Flash Animation
 Answer
the following question by referring to
the attached chart. Which curve or line
represents the total tension of the muscle?
A Curve A
B Curve B
C Curve C
D Curve D
E Curve E
 Answer
the following question by referring to
the attached chart. Which curve or line
represents the total tension of the muscle?
A Curve A
B Curve B
C Curve C
D Curve D
E Curve E
Frequency-tension relation频率-张力关系
Complete dissipation
of elastic tension
between subsequent
stimuli.
S3 occurred prior to
the complete dissipation
of elastic tension from S2.
S3 occurred prior to
the dissipation of ANY
elastic tension from S2.
T e m p o r a l s u m m a t i o n.
Frequency-tension relation
Unfused tetanus非融合性强直收缩:
partial dissipation of
Fused tetanus融合性强直收缩:
elastic tension between
no time for dissipation
subsequent stimuli.
of elastic tension between
rapidly recurring stimuli.
Mechanism for
greater tetanic
tension
Successive action
potentials result in a
persistent elevation of
cytosolic calcium
concentration
Length-tension relation
Short sarcomere:
actin filaments
lack room to slide,
so little tension can
be developed.
Optimal-length sarcomere:
lots of actin-myosin overlap
and plenty of room to slide.
Long sarcomere:
actin and myosin
do not overlap
much, so little
tension can be
developed.
Optimal
length
Click here to play the
Length-Tension Relation
in Skeletal Muscles
Flash Animation
In skeletal muscle, ATP production via substrate phosphorylation
is supplemented by the availability of creatine phosphate磷酸肌酸.
Skeletal muscle’s capacity to produce ATP via oxidative
phosphorylation is further supplemented by the availability
of molecular oxygen bound to intracellular myoglobin.
In skeletal muscle,
repetitive stimulation
leads to fatigue疲劳,
evident as
reduced tension.
Rest overcomes
fatigue, but fatigue
will reoccur sooner
if inadequate recovery
time passes.
Types of skeletal muscle fibers


On the basis of maximal velocities of shortening
 Fast fibers快肌纤维 – containing myosin with high ATPase
activity (type II fibers)
 Slow fibers慢肌纤维 -- containing myosin with low ATPase
activity (type I fibers)
On the basis of major pathway to form ATP
 Oxidative fibers氧化型肌纤维 – containing numerous
mitochondria and having a high capacity for oxidative
phosphorylation, also containing large amounts of
myoglobin (red muscle fibers)
 Glycolytic fibers糖酵解型肌纤维 -- containing few
mitochondria but possessing a high concentration of
glycolytic enzymes and a large store of glycogen, and
containing little myoglobin (white muscle fibers)
Types of skeletal muscle fibers

Slow-oxidative fibers – combine low myosinATPase activity with high oxidative capacity

Fast-oxidative fibers -- combine high myosinATPase activity with high oxidative capacity
and intermediate glycolytic capacity

Fast-glycolytic fibers -- combine high
myosin-ATPase activity with high glycolytic
capacity
Fast-oxidative skeletal muscle
responds quickly and to
repetitive stimulation without
becoming fatigued; muscles
used in walking are examples.
Fast-glycolytic skeletal muscle
is used for quick bursts of
strong activation, such as
muscles used to jump or to
run a short sprint.
Most skeletal muscles include all three types.
Slow-oxidative skeletal muscle
responds well to repetitive
stimulation without becoming
fatigued; muscles of body
posture are examples.
Note: Because fast-glycolytic fibers have significant glycolytic capacity, they are
sometimes called “fast oxidative-glycolytic [FOG] fibers.
 Muscles
containing many type IIA fibers are
called
A Red muscles
B Slow oxidative muscles
C White muscles
D Fast glycolytic muscles
 Muscles
containing many type IIA fibers are
called
A Red muscles
B Slow oxidative muscles
C White muscles
D Fast glycolytic muscles
 The
to
A
B
C
D
E
store of glycogen in the muscle functions
Attenuate blood glucose levels directly
Provide energy for muscle contraction
Provide a source of ketone bodies
Provide structural integrity to muscle
Inhibit muscle contraction
 The
to
A
B
C
D
E
store of glycogen in the muscle functions
Attenuate blood glucose levels directly
Provide energy for muscle contraction
Provide a source of ketone bodies
Provide structural integrity to muscle
Inhibit muscle contraction
Whole-muscle contraction
All three types of
muscle fibers
are represented
in a typical
skeletal muscle,
Fastglycolytic
Fast-oxidative
Slow-oxidative
and, under tetanic
stimulation,
make the predicted
contributions to
the development
of muscle tension.
Flexors(屈肌)
and extensors(
伸肌) work in
antagonistic
sets to refine
movement,
and to allow force
generation in
two opposite
directions.
How can gastrocnemius contraction result in two different movements?
The lever system
of muscles and
bones:
Here, muscle
contraction must
generate 70 kg
force to hold a 10
kg object that is 30
cm away from the
site of muscle
attachment.
Muscle contraction that moves the
attachment site on bone 1 cm
results in a 7 cm movement of
the object 30 cm away from the site;
similar gains in movement velocity occur.
Duchenne muscular dystrophy(Duchenne型肌营养不良)
weakens the hip and trunk muscles, thus altering the
lever-system relationships of the muscles
and bones that are used to stand up.
Case
Duchenne muscular dystrophy is a devastating, progressive disease that occurs in boys; it is
characterized by the progressive necrosis of skeletal muscle fibers and death at an average age
of 16, usually from respiratory failure. It is the second most common genetic disorder in
humans, and there is no specific treatment. The course of the disease includes slow muscular
development, progressive weakness, and frequent contractures. The disease is usually recognized
at ages 2 to 5, and the child is usually confined to a wheelchair by age 12. Laboratory
observations show highly elevated serum concentrations of creatine kinase and other soluble
sarcoplasmic enzymes. Both fast and slow muscle fibers are affected by fiber necrosis and
phagocytosis, balanced by marked regeneration of cells in the early stages of the disease. The
fibers resemble fetal muscles, in terms of their isoenzyme patterns, with marked
dedifferentiation. Fiber death and replacement by fat and connective tissue gradually
predominate. DNA analysis reveals that the disease is caused by the deficiency of a gene on the
X chromosome. The product of the gene is a cytoskeletal protein called dystrophin that forms a
network adjacent to the sarcolemma. Dystrophin is a very large protein (426 kDa). It is a minor
constituent of muscle and links sarcomeres to the sarcolemma via association with a
glycoprotein inserted into the membrane.
Questions
1. Diseases affecting striated muscle cells are uncommon but are devastating and
characteristically lethal. Why?
2. What is the significance of the elevated serum creatine kinase level?
3. Is elevated serum creatine kinase diagnostic for muscular dystrophy?
4. Some muscles are more affected than others. In fact, the muscles of the calves
exhibit a characteristic hypertrophy, whereas the muscles of the upper legs are
weakened. What factors may influence differential responses in a patient whose skeletal
muscle cells lack a functional dystrophin gene?
5. Why is Duchenne muscular dystrophy progressive even though the genetic defect is
present from conception?
6. Why don't girls develop Duchenne muscular dystrophy?
7. Exercise is a major component of the clinical management of Duchenne muscular
dystrophy. What is the rationale?
8. Would the introduction of a functional allele of the dystrophin gene in the affected
cells be a potential treatment that could cure the disease?
Thank you!
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