Lecture - Physiol 4 Skeletal Muscle

Question 1

The neuromuscular junction in skeletal muscle

Explain it

Answer 1

The axon terminal has Scwhwaan cells around it bc it’s myelinated and large diameter etc

So an axon terminal can innervate one muslce fibre or branch out and innervate many (motor unit = axon, plus branches and fibres it innervates).

Ca entered as a result of AP and then vesicles fused and contents released

Some of the ach cleaned up immediately by ach-esterase in the cleft located on the post synaptic membrane.

So this synapse is said to have a high safety factor. Means that regardless of any small variations in the amount of ach that gets across - so much of it is released initially that we are guaranteed to have a post synaptic response. This is unusla bc brain neuron wouldnt behave in that way - need multiple inputs to bring to threshold. Here, guaranteed to get post synaptic AP bc we want muslce to contract each and everytime we want it to (this is a motor system). Hence term high safety factor

So most of the ach doesnt reach receptors bc destroyed by ach-esterase as its trying to get there.

Some of the neurotransmitter escapes away and is destroyed by enzyme cirucalting called ()

Dont want ach leaving MNJ and cirlcuating bc if it comes in contact with any receptors that are part of autonomic NS, it will activate them. Need to restrict ach

What hasnt been destroyed binds to the ionotropic receptors - opens up channel pore and then post synaptic mem becomes depolairsed

“Endplate potential” - equivlanet to local potential in brain neuron. It’s sub-threshold at this point but like,these endplate potentials are large enough to bring about AP in muslce fibre. This is bc muscle fibre has these vg Na-gated channels so it can then generate and propagate AP which sweeps across full lenght of muscle fibre and through T-tubule so all of the fibre gets it

These infoldings in membrane are to increase SA to increase expression of receptors and enzyme

So this is a post synaptic specialisation of muscle fibre membrane. If for some reason this nerve axon disappears and this muscle fibre becomes de-innervated, then the receptors start to spread away to increase opportunity for any re-inervating motor neuron anxon terminals to find muscle fibre. They’ll establish new endplate.

Question 2

What are 7 special features of the NMJ?

Answer 2

1. Has nicotinic Ach receptors (in like autonomic nervous system, you have muscarinic ach receptors)
   - means it’s permeable more to Na than K+ and Ca2+. The net effect = membrane pot becomes depolarised when acetylecholine gated ion channels open
2. Transmission is terminated by Ach-esterase in the cleft. The choline is taken back up for re-synthesis into Ach. This is unusual bc usually you take the whole thing back, not break it up.
   - As soon as Ach enters, this enzyme busies itself in cleaving it from original constituents. Releases choline and that is taken back up into terminal. In brain, neurotransmitter itself is taken back up, repacakged and reutilised. But here, excessive amount released and need to mop it up quickly so cant take it whole back into bouton. This is so the MNJ can run at high frequency and every signal is individual without residual Ach left in the cleft. This is bc tension developed by muscle determined by frequncy of signals coming in.
3. Normally, enough Ach released by a single AP to initiate an AP in 􀀁
   muscle (unlike most synapses). i.e. high ‘safety factor’.
4. During a rapid sequence of many AP’s in nerve, less Ach released per AP; 􀀁
   Normally, there is always still enough for AP in muscle (But see case, Mrs MG)􀀁
   -MG = autoimmune destruction of the post-synaptic receptors

So there are fewer receptors

Initially there is plenty Ach to activate muslce each time

But overtime (normally) with reptitive activaton, as you go on firing, there is less decrease in Ach available to be released but still enough

But if NMJ challenged by lesser receptors then not enough recep to guarantee that the post synap will respond each and everytime to get activation

So with MG, repetitive activation = less and less Ach and since already low on receptors, see weakness after activaiton.

5. End-plate is in middle of muscle, AP propagates away on both sides. Innervation maintains integrity.􀀁
   - strucute of NMJ is dependent on neuron releasig ach at that site (on even minute releases of ach - single vesivular fusion: release small packets of neurotransmitter and this is part of maintence to maintain integritiy of the strucutre)
6. AP in muscle longer duration than nerve, due to longer repolarisation phase
   - Useful bc part of what is driving tht muslce to generate tension is the Ca entering during AP. So most of Ca is released from internal stores but it has a longer repol phase - that we dont just have K channels invoved in repol, also hv Cl channels
7. AP in skeletal muscle uses Cl- channels to assist repolarisation (e.g. Cl- channelopathy).
   - Both K and Cl channels used in repol

Question 3

Describe/draw in your head these things in a muscle fibre:

1. Sarcolemma
2. Myofibril
3. Myofilaments
4. Mitochondria
5. T-Tubule
6. Sarcoplasmic Reiculum

Answer 3

1. Membrane boundary around fibre
2. Within fibre
3. Constituion of myofibril is actin and myosin
4. Red and white msucles etc. Red - filled with mito and BV but very energetically demanding for long term use
5. It is invaginating and has a contrinuity - part of boundary membrane diving down into strucute of muslce fibre all the way through. Very closely opposed to the intracellular srtucuture (sarc reticulum). So reticulum has Ca stores and T tubulue brings AP down to electrically activate reitiulum
6. Reticulum = system of/interconnecting wires/pipes which guarantees Ca release will happen. So it’s tubing in muslce that guarantees that internal Ca release will happen

Question 4

Excitation contraction coupling:

1. Explain it in brief terms
2. What does Ca do?
3. What does summation of all these interactions lead to?
4. So compared to muscle’s AP (5ms), it has a longer duration for the twitch. What two reasons for this
5. What happens if more AP arrive before twitch finished?

Answer 4

1. AP arrives, travels down T-tubule, voltage sensor is activated and then Ca channel in sarcoplasmic reticulum opens and then you get contraction (read slide 5 for more info)
2. Ca2+ —> moves troponin off actin, allowing myosin heads to interact, myosin 􀀁
   head flexes, force exerted on actin􀀁
   -While Ca2+ present, myosin heads repeatedly engage, flex, release􀀁
3. Twitch of a muscle
4. Reason one: Time for release/re-uptake of Ca2+􀀁
   Reason two: Energy, stored in muscle elasticity at beginning of twitch, is released at end
5. Bc Ca signalling is rel slow to AP generation and force generation even slower, means many AP can come and add up. 2nd AP will mean Ca accumulates so larger force being generated

Question 5

Myasthenia gravis

1. What is it?
2. What happens in normal neuromuscular transmission?
3. What happens in MG?

Answer 5

1. Autoimmune attack on neuromuscular Ach receptors
   - More than just fatigue. The amount of Ach avaialbale is falling slightly and there arent enough recpeots to deal with that to not all fibres activating so the ones doing the work are working at higher frequency so get fatigued and over time you’ll reduce the fibres getting activated. Motor units dropping out of fucntion
2. Although Ach release falls slightly with repetitive activation, normal numbers of Ach receptors ensure that a muscle action potential
   always occurs.
3. Number of functional Ach receptors is reduced - As
   Ach release diminishes with repetitive activation,
   neuromuscular transmission eventually fails