Cardiac mitochondrial genes and their products may be different to those of skeletal muscle though. They evolved needing to never rest, while skeletal muscle can and does rest, generally all of it for 8 hours/day (diaphragm excluded).
Yes, I think would expect that.
But I don't know of good evidence of mitochondrial abnormality in muscle in very severe ME/CFS and people with severe ME/CFS not infrequently improve to a stable state of more moderate illness. Some have more than one bout severe illness too.
If ME/CFS was an intrinsic degenerative process in muscle (like a mitochondrial myopathy) then we would expect progressive deterioration without improvement. My picture of the time course I ME/CFS tells me that it must be due to a regulatory disturbance in a system that can shift either up or down through positive or negative feedback. The two systems that are complex enough for that are the central nervous system and the immune system. The relation to infection strongly suggests the immune system is involved.
As analogy, we see a fairly similar situation in RA, which is due to dysregulated antibody production. Many patients gradually deteriorate but remission is not rare and many stabilise even if they have damage.
If an immune reaction was occurring within muscle itself we would expect to get a raised CK and histopathology. Myasthenia is more subtle but even there, EM shows complement mediated changes at end plates.
Which makes me consider the likelihood that nothing much is going on at all in muscle other than that soluble immune signals or perhaps neural signals are inhibiting muscle function either by sensitising to pain and fatigue sensations or by shifting metabolic pathways in a way that prevents very vigorous use. I would like to know what happens in flu myalgia and I cannot find any useful data on PubMed.
Clearly if immune cytokines were adapted to suppressing skeletal muscle use - which would make sense to limit activity and spreading disease - they would be adapted to sparing heart tissue. So muscle mitochondria might be sensitive to certain cytokines and not heart.
So if the immune cytokines are the alarm signals we use in flu and which are being used without good reason in ME/CFS, do we need to invoke more alarm signals from altered metabolism in muscle? Why not just the cytokines that sensitise to pain and fatigue?
But PEM does need a bit more explanation here. If nothing much is going on in muscles why does use produce PEM? The puzzle for me in invoking the metabolic shift is that one would expect that to produce signals immediately. If you run 800 metres your muscles start to burn during the race. People with ME/CFS do describe being unable to continue doing things but time and again I hear the reason people give for the disability in severe ME/CFS as the increased occurrence of delayed PEM.
One possibility is that muscle use normally generates cytokine signals that encourage a period of macrophage and CD8 T cell surveillance in the next 48 hours - and we know that is likely to be the case from studying normal muscle training. Those cytokines may amplify the ones coming from the immune system.
Another possibility is that the danger/illness signalling response involves autonomic neural circuitry and the hypothalamus and is quite sophisticated in the way it allows muscle usage over time. It might well be designed to inhibit activity but in a flexible 'trade-off' way that allows one to struggle home to the cave from one's day tracking animals to eat and then collapse in a heap. A bit like your hypothalamus will allow you to overeat if the food is really tasty (that chocolate mousse) but will then tell you you shouldn't eat anything for 8 hours. Maybe muscle usage in the face of inhibitory signals racks up adrenaline and that allows inhibition to be overcome briefly but also feeds back on to the immune signals to ramp up further?
