Lecture 12: Skeletal Muscle Flashcards
Exam 2
Skeletal muscle is the largest _____?
- The largest contributor to body weight and volume in non-obese people
- Largest container we have within the body
- Need them to behave normally otherwise things get screwed up, very important
How can anesthetics affect skeletal muscle?
We take a lot of skeletal muscles offline with anesthetics
- Volatile anesthetics - reduce amount of muscle activity
- Paralytics - take the skeletal muscles offline
What are the 8 roles of skeletal muscle
- Largest contributor to body weight and volume in non-obese people
- Locomotion
- Expression
- Communication
- Body temp
- Storage of glycogen
- “Effectors”/neural targets
- Large store of ions, fluid, and proteins
The vast majority of skeletal muscle cells are innervated by how many motor neurons?
Just one
One motor neuron can innervate multiple skeletal muscle cells, very large and branch multiple times
A collection of muscle fibers
Motor unit
What is an example of a skeletal muscle cell that is innervated with more than one motor neuron?
ocular muscles in the eye socket
Where are the cell bodies of motor neurons located?
The anterior horn of the grey matter of the spinal cord
A single neuron that innervates a motor unit
Motor Neuron
- Small mu’s=small mn’s
- Large mu’s=large mn’s
What are the 2 ways to excite motor neurons?
- Descending spinal pathways originating from the brain
- Reflex arcs - sensory info fed into the back of the cord that results in a muscle contraction at the same level of the spinal cord (without traveling back to the brain) so that muscle contraction can occur quickly to withdraw from pain
What is another name for a skeletal muscle cell?
Muscle fiber
What are the contractile elements of skeletal muscle cells? How are they arranged?
Actin and myosin filaments - arranged in tube-like structures
What is the specialized version of the ER called in skeletal muscle cells?
Sarcoplasmic reticulum - sarco = muscle, more developed ER
Where do skeletal muscle cells store Ca++?
The sarcoplasmic reticulum - needs Ca++ for contraction (release internally)
What are transverse tubules? Why are they needed?
An extension of the skeletal muscle cells that allows an AP to move deep into the muscle cells (enfolding); invaginations of the cell membrane
Needed because skeletal muscle cells can be very long (can be over a foot long) and are fairly wide/thick
What are the 4 components of skeletal muscle cells
- Sarcoplasm
- Sarcoplasmic reticulum
- Transverse Tubules - AKA T Tubules
- Actin/myosin filaments
What do we need to know for exam 2 about sarcomere anatomy?
Just need to know that contraction shortens the muscle
Fluid inside muscle cells (like cytoplasm)
Sarcoplasm
What are the structures noted in the picture
Microscopic view of skeletal muscle cells
- Each branch of motor neurons takes care of innervation for skeletal muscle fibers
- Each fiber has NMJ associated with it (balls in pic)
- Some only have one motor neuron for several skeletal muscle cells
- Have zebra-like (cross-hatch) pattern because of actin and myosin filaments
What are the invaginations that increase N-M junction surface area?
Clefts
What are the 2 types of clefts on the skeletal muscle cell?
- Primary: only one enfolding
- Secondary: more than one enfolding
What is located in the membrane of skeletal muscle clefts?
ACh receptors towards the surface of the cleft, closer to the neuron
Concentrated V-G Na+ channels on the inside of clefts and the other side of ACh-R
What surrounds motor neurons?
Wrapped in myelin, maintained by Schwann cells that hang out at the terminal end of motor neurons; Schwann cells manage the myelin in the motor neuron back to the spinal cord
What is the role of mitochondria in the NMJ?
The skeletal muscle cells and motor neurons both have a lot of mitochondria located near the NMJ
mitochondria in the presynaptic terminal produce acetate. Acetate combines with recycled choline into acetylcholine (ACh)
How many ACh-R are there? How many are activated during an AP? How much ACh is needed?
ACh receptors - have 5 million at each NMJ
- About 500,00 activated during a typical AP ~10%
- Need to be producing at least 1,000,000 ACh from motor neuron - usually twice that in reality
Why is more ACh released than what is needed by the motor neuron?
- Some get broken down by AChesterase before reaching receptors
- Some bind to receptors and only have 1 ACh molecule bound and therefore can’t activate the receptor (need 2 ACh)
What is the function of AChesterase?
Breaks down ACh via hydrolysis (ACh → acetyl + choline)
Once broken down to acetyl and choline, no more effect on the ACh receptors
Limits length of depolarization from motor neuron - finite time period so resetting can happen
What does the motor neuron do with acetyl and choline after AChesterase breaks apart ACh?
Choline is moved back into motor neuron via choline-sodium transporter and Choline ATPase pumps
Acetyl recycled too but not as much known about mechanism
Where is AChesterase produced and housed?
Produced by the skeletal muscle and fastened to skeletal muscle at the NMJ
What are other ways to describe acetyl?
Acetate, a very small starch group
How are acetate and choline made in the motor neuron?
- Mitochondria produces acetate and ATP
- Can store extra choline in cell wall (phosphatidylcholine)
What is underneath the NMJ and clefts in the skeletal muscle?
Contractile elements - myosin and actin
Why doesn’t K+ want to exit the skeletal muscle cell through open ACh-R, even though it can?
K+ probably would want to leave via leak channels instead (easier)
How many subunits are there on nACh-R?
- 2 Alpha subunits - Both alpha subunits must bind ACh to open the ion channel
- 1 Beta subunit
- 1 Delta subunit
- 1 Epsilon subunit
What is the name of the first nACh-R antagonist? Where was it found?
Curare - paralytic found in rainforest, used to paralyze prey; not used clinically now
- Most non-depolarizing muscle relaxant (NDMR) paralytics are modeled after Curare MOA
- Only need one to bind to each receptor to block the channel, antagonist; stop AP from starting in the skeletal muscle
How does ACh leave the motor neuron? What is this mediated by?
Exocytosis, mediated by Ca++
(SNAP and SNARE proteins)
What are the components of skeletal muscle calcium signaling?
- SR Calcium Release
- Depolarization
- Repolarization
- Ryanodine (RyR) Receptors
- SERCA pumps
What are the different types of channels seen in a skeletal muscle cell?
Same as normal cell -
V-G Na+ channels
V-G K+ channels
K+ leak channels
Na+ leak channels (less than K+)
What are the channels that cause an AP in a skeletal muscle cell?
Same as normal cell -
V-G Na+ channels
V-G K+ channels
How do skeletal muscles know when to respond to an AP?
DHP (dihydropyridine) receptors that sense the voltage changes in the cell wall
- Not really a receptor but a sensor
How do DHP receptors respond to a change in voltage?
Voltage sensor senses AP → has physical connection to Ca++ release channel on SR - tugs on attachment (looks like a spring), removing obstruction from Ca++ being released (pops the cork), liberating Ca++ to inside skeletal muscle → contraction with actin and myosin
- some Ca++ comes from outside cell too
Where are SRs located?
Fairly close to the cell wall, close to T-tubules
- SR is the yellow portion surrounding the T-tubules
Where are DHP receptors located?
In cell wall and in T-tubules
Some Ca++ channel blockers are _______
dihydropyridine Ca++ channel blockers
DHP receptors look a lot like what?
V-G Ca++ channel; lets Ca++ in from SR instead of outside of the cell
However a small amount of Ca++ comes from outside cell too
What is the name of the Ca++ release channel on the SR?
Ryanodine (RyR) Receptors
What chemicals are RyRs sensitive to?
ryanodine
Are RyRs receptors?
Not really a receptor in function in the body because it is physically attached to DHP receptor
Called receptors because they open in response to ryanodine binding
How does the Ca++ get put back into the SR after an AP?
SERCA pumps - sarcoendoplasmic reticulum calcium ATPase (SERCA) pump
- need ATP because Ca++ going against the concentration gradient
What are the steps to skeletal muscle E-C coupling?
- Motor neuron depolarizes (from brain or reflex arcs)
- Ca++ influx into motor neuron (P-type Ca++)
- ACh vesicles fuse to presynaptic neural cell wall/membrane
- ACh secreted by presynaptic neuron (into NMJ)
- ACh interacts with nACh receptors
- Na+ comes in (#1); Ca++ comes in (#2)
- Local Na+ and Ca++ influx generates end plate potential (EPP)
- EPP in a physiologic “setting” always causes an action potential in skeletal muscle; Local depolarization→AP
- Action potential spreads down muscle fibers in both directions (←AP→) via V-G Na+ channels
- Muscle depolarization sensed by dihydropyridine “receptors”/sensors (DHP)
- Dihydropyridine sensors pull on ryanodine receptors (RyRs)
- Ca++ influx into sarcoplasm
- After AP, Ca++ tucked back into SR via SERCA, then muscle stops contracting
When does a skeletal muscle stop contracting?
Once Ca++ tucked away back into SR
What is the local depolarization that generates an AP called? Where does it occur?
End plate potential (EPP) - NMJ
- Occurs when nACh-R opens and allows local Na+ and Ca++ influx
What is myasthenia gravis?
- Condition where the patient’s body generates antibodies to nACh-R
- Immune system response to inflammation or genetic anomaly with thymus gland
- Gets worse throughout the day (better in the morning, worse in the evening)
How does myasthenia gravis affect skeletal muscle?
Antibodies park themselves on top of nACh-R
- The immune system comes in and destroys receptors
- Over time, clefts become scarred over
- Fewer nACh-R and V-G Na+ channels
- Can’t fire an AP
What are the treatments for myasthenia gravis?
- Remove thymus gland
- Plasmapheresis
- Acetylcholinesterase inhibitors (-stigmine)
How does plasmapheresis work to treat MG and LEMS? What’s the downside?
Plasmapheresis removes circulating antibodies
- can’t just remove one type of antibody from blood → can be bad
How do acetylcholinesterase inhibitors treat myasthenia gravis?
Inhibitor AChesterase, keeping ACh around longer, increasing the likelihood of ACh binding to receptors
Why can’t acetylcholinesterase inhibitors be used to treat LEMS?
There’s no ACh in the synapse because P-type Ca++ channels are attacked, so ACh is never released from motor neuron
What is LEMS or ELMS?
Lambert-Eaton Myasthenic Syndrome
- Parody of plastic (paraneoplastic) syndrome - develops after cancer (especially lung cancer)
- Antibodies to P-type Ca++ channels, preventing ACh release from vesicles
What are the treatment options for LEMS?
- Plasmapheresis
- Remove lung tumor
- Drugs to block K+ channels
Drugs used to treat LEMS are fairly _____
dangerous - V-G K+ channel blockers unsafe because not specific for muscle cells only → cardiotoxic
________ isn’t a good K+ channel blocker
Amiodarone - fairly safe because not very good
How do drugs used to block K+ channels treat LEMS?
K+ prevented from leaving cell → more positive membrane potential → longer depolarization of motor neuron → allows more time for Ca++ to come in through P-type Ca++ channels → increasing ACh release
How do P-type Ca++ channels work?
Don’t have an inactivation gate
- Open when cell depolarized, closed when cell is repolarized
What are the drugs that are used to treat LEMS?
TEA - tetra-ethyl ammonium
4,5-diaminopyrimidine
When is LEMS treated with K+ channel blockers?
End stage, nothing can be done about the tumor
Succinylcholine includes
2 ACh
The two types of paralytics are
depolarizing and non-depolarizing
Succinylcholine is a _______ paralytic
depolarizing
How long does succinylcholine last?
10 min, longer than ACh
The initial muscle twitch when giving succinylcholine is called _______
fasciculation
Initially, opening of nACh-R causes a depolarization wave → generating a contraction or fasciculation (initial muscle twitching/quiver), because the drug hits different parts of the muscle at different times
Succinylcholine acts to paralyze the muscle by
Sustained depolarization of the skeletal muscle via binding to nACh-R and keeping them open for prolonged period of time, causing constant Na+ leaking into skeletal muscle, preventing V-G Na+ from resetting
How does sux cause Na+ to constantly leak into the skeletal muscle?
All the V-G Na+ channels in the area are stuck in the inactive configuration because the activation gate won’t close, until repolarization happens
nACh-R are only found in the ____
NMJ, nowhere else in skeletal muscle
Ends of the skeletal muscle farther away, so only small area of skeletal muscle is paralyzed
Can AChesterase break down sux?
AChesterase is specific for breaking ester bonds in ACh, can’t destroy succinylcholine (2 ACh) in the same way
What is different about a stroke patient’s skeletal muscle? What would be the consequences of giving sux?
Sustained (+) inside cell causes more K+ to leak out of cell (trying to repolarize) → leaking K+ in the blood increases by K+ levels by 0.5 mOsm/L, okay in healthy individuals
Unhealthy skeletal muscles (denervation injuries or stroke) - generate more nACh-R in places other than just the NMJ → more K+ leaking, widespread → hyperkalemia → heart problems
Differentiate between P-type and L-type Ca++ channels
P-type - primarily found in the motor neurons, don’t have inactivation gate (open when depolarized, closed when repolarized)
L-type - found in the heart and smooth muscle cells, takes longer to open and close (do have them on motor neurons but not needed for ACh release)
T/F: V-G K+ channels are required for repolarization
F - repolarization mostly via K+ leak channels, but V-G K+ make the process faster
LEMS symptoms get _____ with activity
better
