Skeletal Muscle Ageing LT5 Flashcards
Compare the loss of muscle strength and muscle mass in mice vs humans
Humans lose muscle strength a lot earlier than muscle mass
Mice keep strength, but muscle mass decreases first because mice have high metabolism
Why may dogs be made an ageing model?
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
What do we need to take into account when treating muscle ageing?
Muscle grow in SIZE not in number
Must treat post-mitotic cells different to proliferating tissue
What can be stored in muscle and for what amount of time?
Lipids and glycogen can be stored in muscle temporarily = transient
So problems arise when these stores are not used
Why are sprinters (genetically gifted) at higher risk of developing ALS?
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
How many myonuclei per mm length of fibre?
100 myonuclei
Muscle fibres are the largest cells in the body
What is the lifespan of myonuclei?
Stable for at least 15 years and might even be permanent in human
What is the conventional strategy for targeting age-related loss of muscle mass?
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
How does the mTORC1 complex assemble and where?
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
What is TSC1/TSC2 needed for?
Vital for regulating cell growth and preventing tumour formation, and their dysfunction is linked to tuberous sclerosis complex
Why is sustained mTORC1 activation detrimental?
Drives muscle ageing because constant protein synthesis occurs and puts strain on proteostasis network
What pre-synaptic structure of NMJ are stained and with what?
Neurofilament marks axons
Synaptophysin marks synaptic vesicles
What post-synaptic structure of NMJ are stained and with what?
alpha-bungarotoxin (BTX) labels AChR
What does DAPI label?
Nuclei in the muscle sections
Describe the difference in appearance of young and aged mice NMJ
Young have continuous pretzel-like post-synaptic structure with corresponding apposed pre-synaptic components
Aged NMJ is fragments into disconnected, discrete AChR clusters
What are the 3 age-induced NMJ alterations?
- Fragmentation of post-synaptic structures = discontinuous AChR fragments
- Reduction in number of post-synaptic myonuclei
- Loss of innervation
What does NCAM mark?
Used as biomarker for myofibre denervation
What is NCAM?
Glycoprotein highly expressed at the NMJ
It accumulates intracellularly in the skeletal muscle upon denervation
What was seen, due to the sex-specific effect of ageing on NMJ structural modification?
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
What does the similar morphology of pS6- and NCAM-positive fibres suggest?
Likely S6-positive fibres are denervated
This suggests that mTORC1 activation could be CAUSE or CONSEQUENCE of damaged myofibres
What occurs with deletion of Tsc1?
Hyperphosphorylation of S6 and 4EBP1 in skeletal muscle
What happened in 12month TSC1mKO vs 28m old control mice?
AChR cluster fragmentation was more pronounced in 12mKO mice
No difference observed between the two for post-synaptic myonuclei
What does similar level of post-synaptic myonuclei suggest?
Post-synaptic myonuclei number had already declined in NMJs by 12 month sof age
Might explain lack of effect in KO mice
What implies that activation of mTORC1 is driver for muscle degernation and denervation?
TSC1mKO mice = chronics mTORC1 actvation
These mice CSA of NCAM-postivie myofibres was larger than control
In TSC1mKO mice the difference in NMJ fragmentation between male and female was noted subtly, what does this suggest?
mTORC1 hyperactivation could accelerate and drive NMJs fragmentation
