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“Walk-Along” Theory
Figure 6-7; Guyton & Hall
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U N I T II
Textbook of Medical Physiology, 11th Edition
Chapter 6:
Contraction of Skeletal Muscle
Slides by Thomas H. Adair, PhD
GUYTON & HALL
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Anatomy of Skeletal Muscle
Gross organization:
Figure 6-1; Guyton & Hall
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Cellular Organization
Muscle fibers
• single cells
• multinucleated
• surrounded by the
sarcolemma
Myofibrils
• contractile elements
• surrounded by the
sarcoplasm
Cellular organelles - lie between
myofibrils (mitochondria,
sarcoplasmic reticulum etc.)
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Figure 6-1; Guyton & Hall
Molecular Organization
Figure 6-1; Guyton & Hall
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The Sarcomere
sarcomere
A band
H zone
Z disc
M line
I band
thick filament (myosin)
thin filament (actin)
titin (filamentous structural protein)
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“Sliding Filament” Mechanism
Contraction results from the sliding action of
interdigitating actin and myosin filaments
RELAXED:
CONTRACTED:
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The Actin Filament
− the I band filament
− tethered at one end at
the Z disc
− 1 mm long: v. uniform
nebulin forms guide for
synthesis
Figure 6-6; Guyton & Hall
F-actin
• double-stranded helix
• composed of polymerized G-actin
• ADP bound to each G-actin
(active sites)
• myosin heads bind to active sites
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tropomyosin
• covers active sites
• prevents interaction
with myosin
troponin
• I - binds actin
• T - binds tropomyosin
• C - binds Ca2+
The Myosin Molecule:
• two heavy chains (MW 200,000)
• four light chains (MW 20,000)
• “head” region - site of ATPase activity
Figure 6-5; Guyton & Hall
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Mechanism of Muscle Contraction
Theory:
Binding of Ca2+ to
troponin results in a
conformational change
in tropomyosin that
“uncovers” the active
sites on the actin
molecule, allowing for
myosin to bind.
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“Sliding Filament” Mechanism
Contraction results from the sliding action of
interdigitating actin and myosin filaments
RELAXED:
CONTRACTED:
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Neuromuscular Transmission
- The Neuromuscular Junction -
Figure 7-1; Guyton & Hall
• Specialized synapse between a motoneuron and a
muscle fiber
• Occurs at a structure on the muscle fiber called the motor
end plate (usually only one per fiber)
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Neuromuscular Junction (nmj)
Synaptic trough: invagination in
the motor endplate membrane
• Synaptic cleft:
− 20-30 nm wide
− contains large quantities
of acetylcholinesterase
(AChE)
• Subneural clefts:
− increase the surface area
of the post-synaptic
membrane
− Ach gated channels at tops
− Voltage gated Na+ channel
in bottom half
Figure 7-1; Guyton & Hall
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The Motoneuron – vesicle formation
• Synaptic vesicles: are formed from budding Golgi and are
transported to the terminal by axoplasm “streaming”
(~300,000 per terminal)
• Acetylcholine (ACh) is formed in the cytoplasm and is
transported into the vesicles (~10,000 per)
• Ach filled vesicles occasionally fuse with the post-synaptic
membrane and release their contents. This causes
miniature end-plate potentials in the post-synaptic
membrane.
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The Motoneuron - ACh Release
3
1. AP begins in the ventral
horn of spinal cord.
2. Local depolarization opens
voltage-gated Ca2+ channels.
3. An increase in cytosolic Ca2+
triggers the fusion of ~125
synaptic vesicles with the
pre-synaptic membrane and
release of ACh (exocytosis).
1
AP
2
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Ca2+
ACh Release - details
• Ca2+ channels are
localized around linear
structures on the presynaptic membrane
called dense bars.
• Vesicles fuse with the
membrane in the region of
the dense bars.
• Ach receptors located at
top of subneural cleft.
Figure 7-2; Guyton & Hall
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• Voltage gated Na+
channels in bottom half of
subneural cleft.
End Plate Potential and Action Potential
- at the motor endplate • ACh released into the neuromuscular
junction binds to, and opens, nicotinic ACh
receptor channels on the muscle fiber
membranes (Na+, K+, Ca2+).
• Opening of nACh receptor
channels produces an end
plate potential, which will
normally initiate an AP if the
local spread of current is
sufficient to open voltage
sodium channels.
mV
40
0
-40
• What terminates the
process? acetylcholinesterase
-80
0
15
30
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45
mSec
60
75
nAChr
Na channel
Drug Effects on End Plate Potential
- Inhibitors -
“normal”
Curariform drugs
(D-turbocurarine)
• block nicotinic ACh
channels by competing
for ACh binding site
threshold
curare
botulinum toxin
• reduces amplitude of
end plate potential
therefore, no AP
Botulinum toxin
Figure 7-4; Guyton & Hall
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• decreases the release of Ach
from nerve terminals
• insufficient stimulus to initiate
an AP
Drug Effects on End Plate Potential
- Stimulants ACh-like drugs (methacholine, carbachol, nicotine)
• bind and activate nicotinic ACh receptors
• not destroyed by AChE – prolonged effect
Anti-AChE (neostigmine, physostigmine, diisopropyl
fluorophosphate or “nerve gas”)
• block the degradation of ACh
• prolong its effect
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Myasthenia Gravis
Incidence / symptoms:
• paralysis - lethal in extreme cases when respiratory
muscles are involved
• 2 per 1,000,000 people / year
Cause:
• autoimmune disease characterized by the presence of
antibodies against the nicotinic ACh receptor which destroys
them
• weak end plate potentials
Treatment:
• usually ameliorated by anti-AChE (neostigmine)
• increases amount of ACh in nmj
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Lambert-Eaton Myasthenic Syndrome
Incidence / symptoms:
• 1 per 100,000 people / year
• 40% also have small cell lung cancer
• muscle weakness/paralysis
Cause:
• LEMS results from an autoimmune attack against voltage-gated
calcium channels on the presynaptic motor nerve terminal.
• weak end plate potentials
Treatment:
• can be treated with anti-AChE (neostigmine)
• increases amount of ACh in nmj
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Excitation-Contraction Coupling
Transverse tubule / SR System
T-tubules:
• Invaginations of the sarcolemma
filled with extracellular fluid
• Penetrate the muscle fiber, branch
and form networks
• Transmit AP’s deep into the
muscle fiber
Sarcoplasmic Reticulum:
• terminal cisternae and
longitudinal tubules
• terminal cisternae form
junctional “feet” adjacent to the Ttubule membrane
• intracellular storage compartment
for Ca2+
Figure 7-5; Guyton & Hall
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Arrangement of T-tubules to Myofibrils
- Skeletal muscle vs cardiac muscle Vertebrate skeletal muscle:
• Two T-tubule networks per
sarcomere
• Located near the ends of the
myosin filaments (zone of overlap)
Cardiac muscle (and lower animals):
• Single T-tubule network per
sarcomere
• Located at the level of the Z disc
Figure 7-5; Guyton & Hall
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EC Coupling - the “Triad”
• the junction between two terminal
cisternae and a T-tubule
dihydropyridine
receptor: it’s a
voltage sensor
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T-tubule
Terminal
cisterne
of SR
ryanodine Ca2+ release
channel
EC Coupling –
how it works (skeletal muscle)
Sequence of Events:
1.
2.
3.
4.
5.
6.
AP moves along T-tubule
The voltage change is sensed
by the DHP receptor.
Is communicated to the
ryanodine receptor which
opens. (VACR)
Contraction occurs.
Calcium is pumped back into
SR. Calcium binds to
calsequestrin to facilitate
storage.
Contraction is terminated.
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AP
Ca2+ pump
calsequestrin
Clinical Oddity: Malignant Hyperthermia
Symptoms:
• spontaneous combustion
• skeletal muscle rigidity
• lactic acidosis (hypermetabolism)
Cause:
• triggered by anesthetics (halothane)
• familial tendency - can be tested for by muscle biopsy
• constant leak of SR Ca2+ through ryanodine receptor
Why is so much heat
generated?
Our bodies are only about
45% energy efficient. 55%
of the energy appears as
heat.
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Ca pump
ATP
Muscle Mechanics
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Tension as a Function of Sarcomere Length
• Stress is used to compare tension
(force) generated by different sized
muscles
Normal operating
range
1
– stress = force/cross-sectional area
of muscle; units kg/cm2)
• In skeletal muscle, maximal active
stress is developed at normal
0.5
resting length ~ 2 mm
active
stress
(tension)
• At longer lengths, stress declines -
• At shorter lengths stress also
declines • Cardiac muscle normally operates
at lengths below optimal length Copyright © 2006 by Elsevier, Inc.
0
0
1
2
3
sarcomere length (mm)
4
Frequency Summation of
Twitches and Tetanus
Myoplasmic [Ca2+]
Fused tetanus
Force
AP
Time (1 second)
• Myoplasmic Ca2+ falls (initiating relaxation) before development of
maximal contractile force
• If the muscle is stimulated before complete relaxation has occurred the
new twitch will sum with the previous one etc.
• If action potential frequency is sufficiently high, the individual
contractions are not resolved and a ‘fused tetanus’ contraction is
recorded.
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Motor Unit:
A collection of muscle fibers innervated by a single motor neuron
• large diameter
• All fibers are same type (fast or
slow) in a given motor unit
• Small motor units (eg,larnyx, extraocular)
− as few as 10 fibers/unit
− precise control
− rapid reacting
• Large motor units (eg, quadriceps muscles)
− as many as 1000 fibers/unit
− coarse control
− slower reacting
• Motor units overlap, which provides
coordination
• Not a good relation between fiber type
and size of motor unit
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Relationship of Contraction
Velocity to Load
no afterload:
• maximum velocity at
minimum load
A
increased afterload:
• contraction velocity
decreases
B
contraction velocity is zero
when afterload = max force
of contraction
A: larger, faster muscle (white muscle)
B: smaller, slower muscle (red muscle)
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Types of Skeletal Muscle
- speed of twitch contraction •
Speed of contraction determined by
Vmax of myosin ATPase.
–
High Vmax (fast, white)
• rapid cross bridge cycling
• rapid rate of shortening
(fast fiber)
–
•
•
Figure 6-12; Guyton & Hall
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Low Vmax (slow, red)
• slow cross bridge cycling
• slow rate of shortening
(slow fiber)
Most muscles contain both types of
fiber but proportions differ
All fibers in a particular motor unit
will be of the same type i.e., fast or
slow.
Types of Skeletal Muscle
- resistance to fatigue Slow (red muscle)
•
force (% initial)
•
fast and slow fibers show different
resistance to fatigue
slow fibers
– oxidative
• small diameter
• high myoglobin content
• high capillary density
• many mitochondria
• low glycolytic enzyme
content
Fast (white muscle)
•
fast fibers
– glycolytic
0
5
time (min)
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60
What do the different types do?
•
Fast, slow and intermediate twitch
type muscle can be identified by
histochemistry.
Fast-twitch
slow-twitch
Marathon
Runners
18%
82%
Swimmers
26
74
Average
man
55
45
 Different people have different
Weight
Lifters
55
45
 There is little evidence that training
Sprinters
64
37
Jumpers
63
37
•
•
•
In any muscle there will be a mixture
of slow and fast fibers.
Motor units containing slow fibers
will be recruited first to power
normal contractions.
Fast fibers help out when particularly
forceful contraction is required.
proportions of these types.
alters these proportions in humans.
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Conversion of Fiber Type
- fast to slow -
• Anterior tibialis –
–
–
–
–
left AT
Predominantly fast twitch (upper)
Stains light: few mitochondria
Few, small capillaries
Large fibers
• Electrical stimulation (10 Hz) via
motor nerve (60 days)
– Stimulating fast muscle at the pace of a
slow muscle converts fast twitch fibers to
predominantly slow twitch fibers (lower)
– Stains dark: more mitochondria
– Many, large capillaries
– Larger fibers
right AT
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Muscle Contraction - force summation
Force summation:
increase in contraction
intensity as a result of the
additive effect of individual
twitch contractions
(1) Multiple fiber
summation: results from an
increase in the number of
motor units contracting
simultaneously (fiber
recruitment)
Figure 6-13; Guyton & Hall
(2) Frequency summation: results from
an increase in the frequency of
contraction of a single motor unit
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Muscle Remodeling - growth
• Hypertrophy (common, weeks)
hypertrophy
– Caused by near maximal force
development (eg. weight lifting)
– Increase in actin and myosin
– Myofibrils split
• Hyperplasia (rare)
– Formation of new muscle fibers
– Can be caused by endurance training
• Hypertrophy and hyperplasia
lengthening
hyperplasia
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– Increased force generation
– No change in shortening capacity or
velocity of contraction
• Lengthening (normal)
–
–
–
–
Occurs with normal growth
No change in force development
Increased shortening capacity
Increased contraction velocity
Muscle Remodeling - atrophy
atrophy
• Causes of atrophy
weeks
–
–
–
–
–
Denervation/neuropathy
Tenotomy
Sedentary life style
Plaster cast
Space flight (zero gravity)
• Muscle performance
months/
years
– Degeneration of contractile proteins
– Decreased max force of contraction
– Decreased velocity of contraction
• Atrophy with fiber loss
atrophy with fiber loss
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– Disuse for 1-2 years
– Very difficult to replace lost fibers