Muscle I, II, III Flashcards
1
Q
What are the three classes of muscle?
A
Skeletal, cardia, and smooth
2
Q
What is a myofiber?
A
Long cylindrical cell also called a muscle fiber
3
Q
What is myofiber diameter?
A
50-100 um (and several cm long)
4
Q
How many nuclei in skeletal muscle cell?
A
Hundreds
5
Q
Where are skeletal muscle cell nuclei located?
A
Periphery (out of the way of the business of being a muscle).
6
Q
What does it mean if a muscle cell has a centrally located nucleus?
A
Fiber is damaged and/or undergoing repair
7
Q
Why is skeletal muscle striated in appearance?
A
Precise and repeating alignment of myofilaments
8
Q
What are three types of fibers found in skeletal muscle?
A
Slow twitch and 2 fast twitch
9
Q
What is the “checkerboard” pattern in skeletal muscle?
A
Staining shows the random distribution of fiber types in a muscle.
10
Q
What happens to the “checkerboard” pattern in skeletal muscle, and why?
A
It can change over time if the muscle is partially denervated and subsequently reinnervated.
11
Q
How is cardiac muscle different from skeletal muscle?
A
Much smaller in diameter, shorter, only one nucleus
12
Q
What is a distinguishing feature of cardiac muscle?
A
Intercalated discs
13
Q
What functions do intercalated discs in cardiac muscle serve?
A
1) Physically ties together adjacent cells so they don’t pull apart when contracting.
2) Contain gap junctions for the transmission of electrical current from one cell to the next.
14
Q
Why do intercalated discs of the cardiac muscle contain gap junctions?
A
Current transmission from one cell to the next for action potential propagation (synchronous contraction).
15
Q
How many nuclei are in smooth muscle cells?
A
One
16
Q
What diameter are smooth muscle cells?
A
2-5 um (smallest diameter muscle fibers in body)
17
Q
Describe smooth muscle shape
A
Not striated, but rather spindle shaped with the nucleus near the center
18
Q
What is the basic unit of contraction in striated muscle?
A
Sarcomere
19
Q
Describe sarcomeres
A
Series of repeating units in striated muscle that are the basic unit of contraction. Defined as extending from one Z line to the next Z line.
20
Q
How does a sarcomere shorten in length?
A
Thick and thin filaments slide past each other.
21
Q
What is a myofibril?
A
Bundle of contractile filaments in a muscle fiber.
22
Q
What covers each myofibril?
A
Network of sarcoplasmic reticulum
23
Q
What are the two primary (structural) fibers in a myofibril?
A
Actin (thin filament)
Myosin (thick filament)
24
Q
What are the regulatory proteins in a myofibril?
A
tropomyosin and troponin
25
What are the two forms of actin?
G-actin (globular-single units)
| F-actin (filamentous)
26
What type of actin makes up thin filaments in myofibrils?
F-actin (filamentous)
27
Describe the structure of filamentous actin (F-actin)
Double stranded and helical, like two strings of pearls held side by side and twisted)
28
How long is each thin filament in a myofibril?
1 um
29
Describe the shape of tropomyosin
rod shaped
30
How does tropomyosin interact with actin
Binds to 6-7 actin molecules of one strand
31
Where is troponin bound?
One end of a tropomyosin
32
What are thick filaments made of?
myosin
33
How big is the myosin protein?
470,000 Daltons
34
Describe the structure of myosin
Six proteins in three pairs
- one pair of large, heavy chains
- two pairs of small, light chains
35
Describe the heavy chain of the myosin protein
Forms a long alpha-helical region with a globular head. The alpha-helical regions of each of the heavy chains wraps around the other to form a long rod with the globular heads near each other.
36
What is the position of the light chains in the thick filament
Not exactly known, but are "associated" with the globular heads of the heavy chains.
37
How long are thick filaments in myofibrils?
1.6 um, contain 300-400 myosins
38
Why are thick filaments 1.6 microns long, while thin filaments are 1.0 microns long?
Not known!
| But perhaps regulated by additional proteins that have been identified as associating with the thick and thin filaments
39
What region of the thick filament interacts with actin?
The myosin heads
40
Where is the ATPase activity located in a myofibril?
At the actin-myosin junction
41
What prevents the binding of myosin to actin?
In the relaxed state, the binding site on actin is covered by tropomyosin.
42
What uncovers the actin binding site?
As intracellular free calcium rises, troponin binds Ca++ and undergoes a conformational change. Because troponin is bound to tropomyosin, tropomyosin also undergoes a conformation change and exposes the binding sites on actin. This allows myosin to bind to actin
43
When does myosin use ATP?
After the "pull stroke," myosin remains bound to actin until ATP binds to it, allowing dissociation from actin via ATP hydrolysis.
44
How would you characterize myosin when it initially binds to actin?
Like a pre-coiled spring, ready to act.
45
Describe the motion of the myosin head
It rotates relative to the neck region where the light chains bind.
46
What is the magnitude of the force exerted by myosin on actin?
5 picoNewtons (pN)
47
By how much does a sarcomere shorten for one pull of a myosin head?
about 8 nanometers
48
How does myosin release actin after its pull stroke?
Needs ATP to bind to it, which simultaneously recoils myosin for another pull stroke
49
How does a muscle shorten by several centimeters?
Lots of linearly summated sarcomeres working together, each shortening by 8 nm, and many repeated actin-myosin interaction cycles per contraction
50
How fast does fast twitch muscle turn over?
About 20 times per second
51
How fast does slow twitch muscle turn over?
About 5 times per second
52
How is smooth muscle contraction different from skeletal and cardiac?
No troponin, but Ca++ is still key regulatory molecule.
53
What is a cross bridge?
It's the structure that is formed when the heavy chain reaches out and binds to actin filament via the myosin head
54
Describe the Ca++ chain of events in smooth muscle contraction
1) Increased Ca++ --> bind calmodulin
2) Ca-calmodulin binds CaM kinase, activating it
3) light chain on myosin head phosphorylated
4) phosphorylated myosin binds actin to generate force
5) ATP hydrolysis resets cycle
55
What is the speed of slow muscle contraction compared to skeletal muscle or cardiac muscle contraction?
Slow (up to 1 second to generate full force)
56
How is Ca++ removed from smooth muscle cell?
Ca++ pumps and Na-Ca exchangers in the sarcolemma
57
What happens when Ca++ is removed from smooth muscle cell?
CaM kinase is inactivated, subsequently a phosphatase dephosphorylates myosin
58
What can smooth muscle do that skeletal muscle does not?
Can remain bound and locked in a contracted state without consuming ATP (i.e., actin and myosin do not decouple)
59
What is another structural protein (other than actin and myosin) in a myofilament?
Dystrophin protein
60
Mutation in dystrophin gene and protein leads to...
Duchenne muscular dystrophy
61
Describe dystrophin
Large, filamentous protein associated with both the cortical actin beneath the plasma membrane (not the thin filament actin) and the surface membrane. Dystrophin is part of a complex of membrane-spanning proteins that link the cytoskeleton with the extracellular matrix
62
Name some other important proteins found in muscles that maintain the highly ordered sarcomers
Titin, nebulin, alpha-actinin
63
What does titin do?
Enormous protein that links the myosin thick filaments to the Z-line
64
Beyond binding thick filaments to the Z-line, what does titin do?
keeps the myosin thick filaments centered in a sarcomere
65
What protein probably organizes actin thin filaments?
nebulin
66
What is familial hypertrophic cardiomyopathy (FHC)
Majority of people with FHC have mutations in the cardiac myosin heavy chain. Wall of the left ventricle becomes much thicker than normal, results in about half of all cases of sudden death due to cardiac arrest in your athletes.
Can be result of troponin mutation
67
What is the defect in cardiac myosin heavy chain in FHC?
Two regions of the head - one that binds actin and one that binds ATP - have mutations
68
What is the Ca++ concentration in a relaxed muscle cell?
[Ca++]i < 0.1 um
69
Describe muscle cell innervation
one nerve connection, synaptic contact usually near the center of the cell
70
What exceptions are there to the single innervation rule?
Some extraocular eye muscles
71
What triggers the release of acetylcholine (ACh) in the nerve/muscle synapse?
Motor axon action potential
72
What is the neurotransmitter involved in signaling from a motor axon to a muscle cell?
Acetylcholine
73
What is AChR
acetylcholine receptor, on the muscle post-synaptic membrane
74
Describe the AChR
post-synaptic muscle membrane bound ion channel that opens and causes depolarization when activated by acetylcholine. The depolarization opens sodium channels, initiating an action potential
75
How is a muscular action potential different from a nerve action potential?
Muscular action potential propagates in all (both) directions from the neuromuscular junction (endplate)
76
What are the relative times scales for muscular action potential and contraction?
action potential propagation: few msec
| muscle contraction: 50-100 msec
77
Why is it good that the action potential travels much faster than the contraction itself?
Coordinated contraction over several centimeters distance
78
What is the source of Ca++ in striated muscle cells?
Sarcoplasmic reticulum
79
Why is sarcoplasmic reticulum in skeletal muscle necessary?
Ca++ could diffuse in from cell walls via voltage-gated channels, but this would be too slow compared to release from the SR
80
What is the SR?
Sarcoplasmic reticulum, a membrane bound compartment that stores Ca++, very similar to smooth endoplasmic reticulum, for ready release intracellularly
81
What is the transverse tubule?
The t-tubule is the pathway by which an action potential is transmitted to the interior of a muscle cell, but NOT directly to the SR
82
Describe the classic 1958 experiment of Huxley and Taylor
Pushed the tip of an extracellular microelectrode gently against the surface membrane of a muscle cell and locally depolarized the membrane. If the tip was over the opening of a t-tubule, then a local contraction occurred, but not otherwise.
83
What is E-C coupling
Excitation-contraction coupling - the process (only recently elucidated) by which the membrane depolarization in the t-system is translated into Ca++ release from the SR
84
What is the end of the SR called at its contact with the t-tubule?
terminal cisterna
85
What is contained in the terminal cisterna?
calsequestrin protein
86
What does calsequestrin bind?
About 50 Ca++ per molecule
87
How can you characterize the proteins present at the apposition of the SR and the t-tubule
This is the triad region, very electron dense and dark in electron microscopy pictures
88
What condition leads to malignant hyperthermia?
MH is caused by abnormal calcium release channel in the SR
89
What are symptoms of MH?
catastrophic rise in body temperature when given volatile anesthetics such as halothane. About 1/15,000 occurrence.
90
What is the treatment for MH?
Intravenous dantrolene. Can be given by injection prior to anesthesia if patient is known to be susceptible.
91
How does dantrolene work?
Blocks Ca++ release from SR
92
What is central core disease?
CCD is similar to MH, can come from same mutation in
93
How does the anesthetic halothane work on muscles to cause MH?
Alters SR Ca++ channel such that Ca++ release occurs without the normal requirement for a conformational change in the DHP receptor. The steady Ca++ leak from the SR activates the Ca++ ATPase to pump Ca++ back into the SR in a futile, potentially lethal, heat-producing cycle.
94
What protein causes muscular dysgenesis (in mice), and where is it located?
The DHP receptor, part of the triad.
95
Describe attempts at gene therapy treatment for Duchenne muscular dystrophy.
Inject normal myoblasts into cells and hope they fuse and express normal dystrophin protein. Not been successful, as almost all injected cells die.
96
What is E-C coupling dependent on?
The DHP receptor.
97
How is cardiac DHP different from skeletal muscle DHP?
The cardiac DHP receptor is a different gene product, as in, a similar protein made by a different gene. Thus, cardiac muscle can work fine in a subject with a mutation in the gene that codes for skeletal muscle DHP, even though both receptors are sensitive to Ca++.
98
Describe the sequence of events in a single contraction cycle.
1) Ca++ is released from the cisternae of the SR
2) Ca++ diffuses to the myofilaments in a myofibril
3) Ca++ binds troponin, changing its conformation
4) Since troponin is bound to tropomyosin, tropomyosin also changes conformation
5) Tropomyosin conformation change reveals myosin binding site on actin filament
6) Myosin binds actin, performs pull stroke
7) ATP binds myosin to reactivate it (coiled spring)
8) Ca++ ATPase pumps in the SR membrane transport Ca++ back into the SR
9) Cytoplasmic [Ca++] returns to low level (<0.1uM)
99
Summarize action potential -> contraction in skeletal muscle
1) Action potential in motor nerve
2) Acetylcholine (ACh) release
3) ACh receptor binds ACh and opens, causing depolarization
4) Action potential propagates down the fiber
5) Action potential and depolarization also occurs in t-tubules
6) Protein links at t-tubules/SR junction (triad) are altered to allow Ca++ release from SR
7) Ca++ bind to troponin, alters conformation of tropomyosin, alters conformation of tropomyosin and exposes myosin-actin binding site
8) As long as Ca++ and ATP are present, the myosin-actin cycle continues
9) Relaxation: Ca++ ATPase pumps Ca++ back into the SR, lowering cytoplasmic Ca++ and tropomyosin again blocks the myosin-actin binding site.
100
Why do smooth muscle cells lack the t-system and SR?
Smooth muscle fibers (cells) are so narrow in diameter that diffusion from the surface of the cell to the center is sufficiently quick for all intents and purposes.
101
How is cardiac muscle different from skeletal muscle in terms of structure and control of Ca++ release from the SR?
The cardiac Ca++ channel binds Ca. Thus, Ca++ entry is required to trigger Ca++ release by the Ca++ release channel of the SR in cardiac muscle.
102
What is the major regulator of contraction in all three muscle types?
Ca++
103
Discuss length vs tension in muscle fiber contraction
At full sarcomere length, there is almost no overlap between actin filaments and myosin. Thus, myosin heads have very little purchase on actin and very little tension is produced in a pull stroke. Tension increases linearly with fiber overlap until it is at a maximum. The maximum is reached when all available myosin heads can form a cross bridge with actin filaments. As sarcomere length continues to shorten, the actin chains interdigitate and tension falls off
104
What is a motor unit?
A motor unit is the group of muscle fibers innervated by a motor neuron.
105
Where do motor neurons originate?
The spinal cord. Ventral roots, I'd hazard.
106
What happens to muscle that is innervated by a damaged nerve?
Weakness at the bulk level, paralysis at the motor unit level.
107
Which muscle fibers activate when a motor neuron fires an action potential?
All of the fibers innervated by a given motor neuron contract in unison when the neuron gives the signal.
108
Describe motor unit size variability
The size of a motor unit varies not only from muscle to muscle, but also within a single muscle.
Fine motor skill muscles (fingers, extraocular) have small motor units (three to tens of fibers), gross movement muscles have hundreds of fibers per motor unit.
109
Describe the progression of motor unit recruitment
Small motor units are recruited first, and progressively larger motor units are recruited as the strength of contraction is increased. Allows for fine control of movement.
110
Compare cardiac and smooth muscle innervation to that of skeletal muscle.
Both are innervated, but can function without nervous innervation. The innate "excitability" is modulated by excitatory and inhibitory innervation.
111
How are cardiac and smooth muscle electrically different from skeletal muscle?
Cardiac and smooth muscle cells are electrically coupled via gap junctions, while skeletal muscle cells are electrically independent.
112
How are slow, fast, and intermediate skeletal muscle fibers different?
Different myosin isoenzymes, different proportions of mitochondria and oxidative enzymes, different resistance to fatigue, different speeds of contraction
113
How many different types of muscle fiber does a given motor unit possess?
Only one - straight slow, intermediate, or fast twitch fibers. An entire muscle is not homogeneous, though.
114
What to slow oxidative fibers do?
Maintain postural or relatively maintained contractions
115
Which muscle fibers are reddish, and why?
Slow fibers, due to high myoglobin content
116
How is skeletal muscle tension graded (graduated)?
Several ways:
1) Increase frequency of action potentials
2) Recruit additional motor units
3) Change length of muscle (i.e., fiber overlap in sarcomere) (minor effect)
117
How is tension grading in cardiac and smooth muscle different from that of skeletal muscle?
Cardiac and smooth muscle both respond to neurotransmitters and hormone-like molecules. Also, cell length is important in smooth and cardiac muscle since the muscle is not anchored to bone and can change significantly during contraction.
118
What are satellite cells?
Stem cells that are closely associated with each skeletal muscle cell.
119
What do satellite cells provide?
Satellite cells are stem cells and are the source of new myoblasts to repair injured muscle.
120
What happens if a muscle fiber is seriously damaged?
Satellite cells on the surface of that fiber will divide and fuse, forming a new muscle cell
121
What signaling molecules trigger a response in satellite cells?
Many: fibroblast growth factor (FGF), insulin growth factor (IGF), hepatocyte growth factor (HGF), NF-kappa B, nitric oxide (NO), and myostatin (from the TGF-beta family)
122
What factor produced by damaged muscle cells triggers satellite cell proliferation?
leukemia inhibitory factor (LIF)
123
Other than LIF, what regulates the proliferation of satellite cells?
Perhaps connective tissue fibroblasts via some interaction with satellite cells (2011).
124
Which cells prevent premature differentiation of satellite cells?
Fibroblasts
125
What is a prevailing, though unproven, theory about Duchenne muscular dystrophy and satellite cells?
DMD cells are weakened and damaged by the absence of dystrophin protein. Subsequently, satellite cells are continually fusing to repair the muscle fibers until the satellite cells are depleted or lose the ability to keep up with the muscle degeneration.
126
Discuss damage to cardiac muscles
Cardiac muscle does not contain satellite cells. Thus, there is little or no repair of damage after a heart attack. te damaged area contains scar tissue produced by fibroblasts.
127
How does smooth muscle repair itself?
Smooth muscle cells can dedifferentiate, enter mitosis, and regenerate new muscle cells.
128
What is leiomyosarcoma?
A type of smooth muscle tumor resulting from the unregulated proliferation of smooth muscle cells.
129
Where does leiomyosarcoma occur?
Anywhere in the body, since blood vessels contain smooth muscle.
130
What is hypertrophy?
Bigger cells
131
What is hyperplasia
More cells
132
How do muscles respond to exercise (hypertrophy or hyperplasia)?
Hypertrophy. The cross-sectional area of each cell is increased with the formation of new myofibrils, but new muscle fibers are not created.
133
How do muscles atrophy?
Hypotrophy - muscle fibers decrease in size, not number
134
Discuss fast and slow muscle fibers in athletes
Marathoners have many more slow than fast fibers
Sprinters have many more fast than slow fibers
General population is more evenly mixed.
135
Super athletes - genetics or training?
Genetics - fiber types cannot be switched under normal physiological conditions (but can in a lab with all sorts of crazy interventions)
136
What is fatigue?
Medical school plus children plus everything else. Otherwise, reduced performance during prolonged or intense activity.
137
Describe the effects of muscle fatigue
Decrease in force production and speed of contraction
138
What can cause fatigue, in principle?
Any impairment at any point from the motor neuron down to the events at the SR and myofilament interactions.
139
What steps of contraction are most likely to be affected in fatigue?
1) Propagation of the action potential into the t-tubule
2) release of Ca++ from the SR
3) effect of Ca++ on the myofilament interaction
4) force generation by the myofilaments
140
Discuss t-tubule fatigue
At high frequency stimulation, K+ builds up and Na+ is reduced in the restricted space of the t-tubular network. This leads to action potential amplitude reduction or failure in the inner part of the t system. Ultimately, the outer part of a fiber contracts, but the center does not
141
What is the recovery time from t-tubule fatigue?
Seconds - diffusion in the t system is quick
142
How much ATP is burned during muscle contraction?
One for each myosin-actin cycle and one for each Ca++ pumped back into the SR
143
What metabolic changes are observed in muscle fatigue?
Increase in [inorganic phosphate], increase in [creatine] and a decrease in pH (down to 6.5)
144
How is ATP regenerated during strenuous contraction
phosphocreatine
145
What happens to Ca++ binding affinity on troponin during fatigue?
Decreases, possibly due to competition from H+
146
What is the effect of elevated phosphate and hydrogen ions on muscle contraction?
Reduce the force generated by myosin pulling on actin
147
Which smooth muscles contain sarcoplasmic reticulum?
Some, but not all, and not really sure why, since smooth muscle fibers are small and don't need SR to get Ca++ signal saturation
148
What kinds of nerves innervate smooth muscle?
Both sympathetic and parasympathetic
149
What does NO do to smooth muscle?
Triggers relaxation
150
Where is NO produced?
Endothelial cells and some neurons
151
Which smooth muscles does NO act on, and how?
Relaxation of cerebral arteries, coronary arteries, and arterial smooth muscle of the penis.
152
How does NO work to relax smooth muscle?
NO binds to a receptor that increases levels of cGMP
153
How do Viagra and Cialis (i.e., donger magic pills) work?
Prevent breakdown of cGMP, thus enhancing action of nitric oxide.
154
What type of smooth muscles produce action potentials?
Peristaltic or propagating muscles such as the longitudinal muscles of the gut, uterus, and bladder
