Lecture 30 - Metabolic reprogramming of skeletal muscle stem-cells Flashcards
True or False
In quiscent SCs you wont see the volume of mitochondria and the complexity of the network as opposed to active SCs
true
Glycolysis produces intermediates which can be used for what?
what cycle is it?
New biomass for proliferating cells
Pentose cycle:
- producing nucleotides for DNA
- producing phospholipids (essential for membranes)
- AAs - serine, glycine, cysteine
There were approx 3000 genes that were heavily enriched in quiescent satellite cells. meaning upon activation of Satellite cells they were turned off or downregulated. what would these genes be responsible for?
what else has been found in activated SCs?
FA metabolism!. as well as cell adhesion and homeostatic processes
3000 genes that were upregulated in activated SCs. these were needed for:
- glucose metabolism!
-cell proliferation
cell cycle progression
Is glycolysis happening in the quiescent state?
yes, but at very low/basal levels.
once active there is a huge increase - most being used to support the generation of new biomass
histone acetylation does what for transcription?
increases transcription
H4K16ac is an indicator of …
an activated satellite cell
true or False
SirT1 requires NAD to work
true
deacetylates histones = represses transcription
Does the total amount of SirT1 derease with satellite cell activation?
No.
doesn’t explain the increase in histone acetylation.
But NAD is required. and NAD levels are regulated through metabolism
What happens to NAD levels from quiescent –> activated?
why?
NAD+ levels decrease
due to a rapid increase in glycolysis
this directly links the change in metabolism with the histone deaceylation
describe the state of quiescent and activated SCs with respect to metabolism, NAD levels and SIRT1 activity
Quiescent FA oxidation/oxphos high NAD+ High SIRt1 activity = transcriptional repression
Activated Glycolysis low NAD+ Low SIRT1 activity = transcriptional activation
true or false
The majority of proliferating SCs are MyoD+ and committed to the myogenic lineage
proliferating SCs are highly glycolytic
true
raises the question of whether they can be ‘‘pushed back’’ to a stem-like state by altering metabolism
How can we test whether we can induce metabolic reprogramming?
culture media for proliferating cells
- control = glucose
- low glucose
- galactose (becomes energy neutral as it requires ATP to break down - this forces the cell into oxphos using pyruvate)
then measure cellular metabolism and genetic profile
True or false
Glycolysis is increased in cells cultured in galactose
False
it is reduced.
forcing the cell to use oxphos
true or false
inhibiting glycolysis with galactose decreases myogenic specification
true
what is TXNIP?
an essential regulator of glycolysis
acts by inhibiting glucose uptake and conversion to glucose-6-phosphate (first step of glycolytic pathway)
overexpression of TXNIP leads to what?
inhibition of glycolysis
complete stop of cell cycle and proliferation
decline in the expression of MyoD - pushes away from myogenic commitment
G(0) cell state is referring to..
quiescence (reversible G0)
but there is also:
differentiation (irreversible G0)
Senescence (irreversible G0) - happens with age
PKM1 does what?
Pryuvate kinase 1 - promotes movement of phosphoenolpyruvate (PEP) into pyruvate
high levels of PKM1 is associated with increased reliance on..
oxphos
PKM2 has a much ____ afinity for PEP
PKM2 has a much lower afinity for PEP
allows for the build up of PEP and the upstream intermediates
remember these are neccessary for the generation of new biomass
PKM1 will have high levels in _____ cell population
PKM2 will have high levels in _____ cell populations
PKM1 will have high levels in quiscent cell population
PKM2 will have high levels in activated cell populations
The difference between PKM1 and PKM2 is…
one exon
and quiescent cells have more of the PKM1 exon expressed
true or false
overexpression of PKM2 in proliferating SCs blocks the production of lactate and decreases the rate of cell proliferation
false
overexpression of PKM2 in proliferating SCs blocks the production of lactate, but increases the rate of cell proliferation
true or false
it is possible to reprogram previously commited/specified myogenic cells through targeted changes in metabolism
true
