Skeletal Muscle Ageing LT5

Question 1

Compare the loss of muscle strength and muscle mass in mice vs humans

Answer 1

Humans lose muscle strength a lot earlier than muscle mass

Mice keep strength, but muscle mass decreases first because mice have high metabolism

Question 2

Why may dogs be made an ageing model?

Answer 2

They live in the same env so have similar microbiomes

Easier to control dogs physical levels than mice (ask them to sit and stay still)

Downside = dogs live longer than mice

Question 3

What do we need to take into account when treating muscle ageing?

Answer 3

Muscle grow in SIZE not in number

Must treat post-mitotic cells different to proliferating tissue

Question 4

What can be stored in muscle and for what amount of time?

Answer 4

Lipids and glycogen can be stored in muscle temporarily = transient

So problems arise when these stores are not used

Question 5

Why are sprinters (genetically gifted) at higher risk of developing ALS?

Answer 5

Because they recruit more motor neurones to innervate type 2 fibres

In ALS, motor neurons progressively degenerate, and this heightened usage might increase the risk of developing the disease, as the neurons may be more susceptible to damage from the strain of intense physical activity

Question 6

How many myonuclei per mm length of fibre?

Answer 6

100 myonuclei

Muscle fibres are the largest cells in the body

Question 7

What is the lifespan of myonuclei?

Answer 7

Stable for at least 15 years and might even be permanent in human

Question 8

What is the conventional strategy for targeting age-related loss of muscle mass?

Answer 8

Sarcomeres are proteins, so to eat more protein could potentially have more amino acids to use as building blocks

If you could stop catabolism (autophagy), this could potentially stop the breakdown of muscle

Target upstream of proteostasis pathway

Question 9

How does the mTORC1 complex assemble and where?

Answer 9

Assembles on the surface of lysosome because the lysosome may secrete amino acids

mTORC1 is the key sensor of nutritional status and environmental stresses for cell growth and survival

When free components of mTOCR1 are in cytoplasm = INACTIVE

Question 10

What is TSC1/TSC2 needed for?

Answer 10

Vital for regulating cell growth and preventing tumour formation, and their dysfunction is linked to tuberous sclerosis complex

Question 11

Why is sustained mTORC1 activation detrimental?

Answer 11

Drives muscle ageing because constant protein synthesis occurs and puts strain on proteostasis network

Question 12

What pre-synaptic structure of NMJ are stained and with what?

Answer 12

Neurofilament marks axons

Synaptophysin marks synaptic vesicles

Question 13

What post-synaptic structure of NMJ are stained and with what?

Answer 13

alpha-bungarotoxin (BTX) labels AChR

Question 14

What does DAPI label?

Answer 14

Nuclei in the muscle sections

Question 15

Describe the difference in appearance of young and aged mice NMJ

Answer 15

Young have continuous pretzel-like post-synaptic structure with corresponding apposed pre-synaptic components

Aged NMJ is fragments into disconnected, discrete AChR clusters

Question 16

What are the 3 age-induced NMJ alterations?

Answer 16

1. Fragmentation of post-synaptic structures = discontinuous AChR fragments
2. Reduction in number of post-synaptic myonuclei
3. Loss of innervation

Question 17

What does NCAM mark?

Answer 17

Used as biomarker for myofibre denervation

Question 18

What is NCAM?

Answer 18

Glycoprotein highly expressed at the NMJ

It accumulates intracellularly in the skeletal muscle upon denervation

Question 19

What was seen, due to the sex-specific effect of ageing on NMJ structural modification?

Answer 19

Males displayed all 3 age-induced NMJ alterations

But females only showed loss of post-synaptic myonuclei
Did not see fragmentation of post-synaptic structure nor loss of innervation

Question 20

What does the similar morphology of pS6- and NCAM-positive fibres suggest?

Answer 20

Likely S6-positive fibres are denervated

This suggests that mTORC1 activation could be CAUSE or CONSEQUENCE of damaged myofibres

Question 21

What occurs with deletion of Tsc1?

Answer 21

Hyperphosphorylation of S6 and 4EBP1 in skeletal muscle

Question 22

What happened in 12month TSC1mKO vs 28m old control mice?

Answer 22

AChR cluster fragmentation was more pronounced in 12mKO mice

No difference observed between the two for post-synaptic myonuclei

Question 23

What does similar level of post-synaptic myonuclei suggest?

Answer 23

Post-synaptic myonuclei number had already declined in NMJs by 12 month sof age

Might explain lack of effect in KO mice

Question 24

What implies that activation of mTORC1 is driver for muscle degernation and denervation?

Answer 24

TSC1mKO mice = chronics mTORC1 actvation

These mice CSA of NCAM-postivie myofibres was larger than control

Question 25

In TSC1mKO mice the difference in NMJ fragmentation between male and female was noted subtly, what does this suggest?

Answer 25

mTORC1 hyperactivation could accelerate and drive NMJs fragmentation