1. “Walk-Along” Theory
Figure 6-7; Guyton & Hall

2. Contraction of Skeletal Muscle
Chapter 6:
Contraction of Skeletal Muscle
Slides by Thomas H. Adair, PhD

3. Anatomy of Skeletal Muscle
Gross organization:
Nuclei along length of muscle fiber come from satellite cells during formation of fiber.
Figure 6-1; Guyton & Hall

4. Cellular Organization
Muscle fibers
single cells
multinucleated
surrounded by the
sarcolemma
Myofibrils
contractile elements
surrounded by the
sarcoplasm
Sarcolemma = true plasma membrane plus outer cost pf polysaccharide material with collagen fibers that fuses with tendon. The SR is the ER of skeletal muscle. Note error in book – calls this extracellular space in figure legend.
Cellular organelles - lie between myofibrils (mitochondria, sarcoplasmic reticulum etc.)
Figure 6-1; Guyton & Hall

5. Molecular Organization
Figure 6-1; Guyton & Hall

6. The Sarcomere sarcomere A band M line H zone Z disc I band
thick filament (myosin)
thin filament (actin)
titin (filamentous structural protein)

7. “Sliding Filament” Mechanism
Contraction results from the sliding action of interdigitating actin and myosin filaments
RELAXED:
CONTRACTED:

8. The Actin Filament F-actin troponin tropomyosin 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
tropomyosin
covers active sites
prevents interaction
with myosin
almost exactly 1 mm long in vertebrate striated muscle (v. uniform). This is regulated by a thin filament associated protein, ‘nebulin’. Nebulin appears to form a guide that determines how long the actin filament will be.
troponin
I - binds actin
T - binds tropomyosin
C - binds Ca2+

9. 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

10. 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.

11. “Sliding Filament” Mechanism
Contraction results from the sliding action of interdigitating actin and myosin filaments
RELAXED:
CONTRACTED:

12. 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)

13. 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

14. 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.

15. The Motoneuron - ACh Release3
AP begins in the ventral horn of spinal cord.
Local depolarization opens voltage-gated Ca2+ channels.
An increase in cytosolic Ca2+ triggers the fusion of ~125 synaptic vesicles with the pre-synaptic membrane and release of ACh (exocytosis). 1 AP
Ca2+ 2

16. ACh Release - details
Ca2+ channels are localized around linear structures on the pre-synaptic membrane called dense bars.
Vesicles fuse with the membrane in the region of the dense bars.
Ach receptors located at top of subneural cleft.
Voltage gated Na+ channels in bottom half of subneural cleft.
Figure 7-2; Guyton & Hall

17. 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
-40
-80
What terminates the process?
acetylcholinesterase
nAChr
Na channel
mSec

18. Drug Effects on End Plate Potential
- Inhibitors -
Curariform drugs (D-turbocurarine)
block nicotinic ACh
channels by competing
for ACh binding site
reduces amplitude of
end plate potential therefore, no AP
“normal”
threshold
curare
botulinum toxin
Botulinum toxin
decreases the release of Ach
from nerve terminals
insufficient stimulus to initiate
an AP
Figure 7-4; Guyton & Hall

19. 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

20. Myasthenia Gravis Incidence / symptoms: Cause: Treatment:
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

21. 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

22. 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 T-
tubule membrane
intracellular storage compartment
for Ca2+
Figure 7-5; Guyton & Hall

23. 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

24. EC Coupling - the “Triad”
the junction between two terminal
cisternae and a T-tubule
dihydropyridine
receptor: it’s a voltage sensor
T-tubule
Terminal cisterne of SR
ryanodine Ca2+ release
channel

25. EC Coupling – how it works (skeletal muscle) AP Sequence of Events:
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. AP
Ca2+ pump
calsequestrin

26. 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?
Ca pump
Our bodies are only about 45% energy efficient. 55% of the energy appears as heat.
ATP

27. Muscle Mechanics

28. Tension as a Function of Sarcomere Length
sarcomere length (mm) 1 2 3 4
0.5
Stress is used to compare tension (force) generated by different sized muscles
stress = force/cross-sectional area of muscle; units kg/cm2)
In skeletal muscle, maximal active stress is developed at normal resting length ~ 2 mm
At longer lengths, stress declines -
At shorter lengths stress also declines -
Cardiac muscle normally operates at lengths below optimal length -
Normal operating
range
active
stress
(tension)

29. Frequency Summation of Twitches and Tetanus
Myoplasmic [Ca2+]
Force AP
Time (1 second)
Fused tetanus
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.

30. 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
Size of motor unit does not seem to dictate fiber type – extraocular muscle is fast but motor unit is small. Soleus muscle is slow but motor unit is large. Large, fast muscle for sprinting etc have large motor units.
Smaller motor neurones tend to be more tonically active, and to innervate fewer fibres (smaller motor units); the fibres tend to be slow oxidative types.
Large motor neurones tend to be phasically active (silent mostly, with brief intense bursts of activity), and have large motor units, with fast, glycolytic fibres.
Numbers of fibres per motor unit vary from 10 for small muscles with finely graded action (extraocular muscles) to 1000 for large postural muscles.

31. 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)

32. 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)
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.
Figure 6-12; Guyton & Hall

33. - resistance to fatigue -
Types of Skeletal Muscle
- resistance to fatigue -
Slow (red muscle)
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 fibers
glycolytic
force (% initial)
Fast (white muscle)
Fast fibres that are resistant to fatigue are sometimes called ‘intermediate’ or type Iia. Sometimes also FOG for Fast Oxidative Glycolytic or even FR for Fast ResistantThese are quite rare in humans.
Type Iia fibres have high concentrations of myoglobin and oxidative enzymes
cardiac has quite slow myosin ATPase rates and has other properties that make it more similar to type I fibres.
Type IIB or just type II fibres can be called FF for Fast Fatiguing or FG for Fast Glycolytic.
The root cause of experimental (in vitro) fatigue is not known. It appears to be a metabolic limitation but it is not ATP since this is not drastically reduced in exercise exhausted (fatigued) muscle.
In life the muscle is never metabolically fatigued. Exercise is halted before this occurs and this is a central nervous phenomenon. There is pain associated with severe exercise and this and other homeostatic markers (temperature, plasma metabolyte levels) are probably the ‘sensed’ variables. 5 60
time (min)

34. What do the different types do?
Fast-twitch slow-twitch
Fast, slow and intermediate twitch type muscle can be identified by histochemistry.
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.
Different people have different proportions of these types.
There is little evidence that training alters these proportions in humans.
Marathon 18% %
Runners
Swimmers
Average
man
Weight
Lifters
Sprinters
Jumpers
In animals the relative proportions of fibres that are type I can be altered by exercise regimes. There is little evidence of this in man.
Exercise can however influence the biochemical capacities of muscle. For example, aerobic exercise can increase capillary density, myoglobin content and the number of mitochondria. This creates improvement is performance and fatigue resistance. There will also be similar changes to the capacity of the cardiovascular system.
In trained atheletes it appears that performance is ultimately limited by the pulmonary system - supply of oxygen to the muscles is the limiting factor.

35. Conversion of Fiber Type - fast to slow -
left AT
Anterior tibialis –
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

36. 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

37. Muscle Remodeling - growth
Hypertrophy (common, weeks)
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
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
hypertrophy
lengthening
hyperplasia

38. Muscle Remodeling - atrophy
Causes of atrophy
Denervation/neuropathy
Tenotomy
Sedentary life style
Plaster cast
Space flight (zero gravity)
Muscle performance
Degeneration of contractile proteins
Decreased max force of contraction
Decreased velocity of contraction
Atrophy with fiber loss
Disuse for 1-2 years
Very difficult to replace lost fibers
weeks
atrophy with fiber loss
months/
years