I've read this entire thread and I still don't understand how any of this is relevant to the physiology/symptoms of ME/CFS? Maybe
@jnmaciuch can enlighten me?
Agreed with Jonathan, though I think there are still additional missing pieces/contradictions with literature (which, to be clear, is to be expected from any theory so I am not disregarding it out of hand on those reasons). If this theory is correct, you would assume it leads to accumulation of the metabolites which trigger the metabosensing afferents you have brought up mediating central fatigue. As already mentioned, though, I think the link to PEM is a big missing piece here. Like you, I am not convinced brain ammonia levels are sufficient to explain for several reasons (personal opinion, take it or leave it).
I am also particularly thinking of Cara Tomas’s group and their muscle metabolism work, which showed comparable functioning between healthy and ME/CFS via galactose-only oxidative phosphorylation and fatty acid metabolism, both of which would be reliant on acetyl-CoA making it through the TCA cycle. I suppose if it’s a “weak” itaconate shunt it might be compensated by glutamine to some extent [or simply increased throughput through either pathway to counteract lack of efficiency. FAO also does produce some NADH independent of Acetyl-CoA output].
And like I said earlier, I have doubts as to whether a solely parenchymal response would be able to upregulate IRG1 to a sufficient extent. If the initial parenchymal response led to tissue resident macrophage activation during exertion, then I could see it being sufficiently propagated through those macrophages, and the local metabolic depression would be explained by itaconate inhibition of SDH alone or perhaps by those macrophages simply outcompeting parenchymal cells for glucose.
But there are doubts as to whether even high levels of itaconate from macrophages could do this in other cells, and we don’t see other signs of macrophage activation that you would expect from Nf-kB upregulation.
