Can you not give a couple of quick examples again?
I spend hours each day trying to keep with all the discussions here and I am not immediately clear how what has gone before relates to my question here.
I guess the question is that if some signal tells the cells they have to use other pathways might that not be the 'warning signal' that tells the neuromuscular apparatus to reduce activity? Rather than an effect of the cells being forced by something else to shift pathways.
I'll do my best to summarize my working hypothesis briefly. It mostly addresses the question of why some but not all activity triggers PEM, and why a malic acid supplement may have provided me and some others with such substantial increase in functionality.
The malate-aspartate shuttle is the main process responsible for shuttling electrons (H-) between cytosolic and mitochondrial NAD pools. Mitochondrial NADH then begins oxidative phosphorylation at complex I. The G3P shuttle (via FADH2 reducing ubiquinone to ubiquinol) can also do this, though it is less efficient.
If an impairment in the TCA cycle led to reduced levels of malate, or made the malate-alpha ketoglutarate transporter less efficient, this would result in a reduced maximal rate of electron shuttling.
This may not be an issue most of the time if the cell's current ATP demand can be sufficiently maintained with that reduced maximal shuttling rate. If you had not been active in days before the first day of a CPET challenge, even a less-than-ideal rate of shuttling would have allowed sufficient mitochondrial NADH to already be built up to sustain a few minutes of cycling.
However, once you go beyond that rate limit, ATP usage exceeds what can be maintained by malate shuttling. It's like a battery that is being used at the same rate it is being charged.
In those events, additional ATP can be generated outside of oxidative phosphorylation by upregulated beta-oxidation and glycolysis. However, both of those backups produce substantially less ATP per turn than OxPhos (~2 per glucose molecule or ~5 per fatty acid chain as opposed to 32-38 for OxPhos, depending how you count).
Furthermore, we already know that many immune cells, particularly macrophages, are quite sensitive to shifts in metabolism. For example, increased extracellular lactate has been tied to microglial activation in Parkinson's (
source), and impairment of complex I results in macrophages that highly sensitive to stimuli (
source). I suspect that they are mediating immune signaling that drives PEM symptoms.
This system in macrophages is quite complicated--we are also learning that some OxPhos activity (particularly Complex I) is required for ROS generation and upregulation of certain cytokines associated with sepsis, for example (
source). I'm still in the early stages of hypothesis generation, but I feel like this discrepancy may hold the key for why we
don't see vascular inflammation in ME/CFS.
There is much more basic investigative work to be done here, but I think this provides a plausible link between exertion and delayed PEM reactions that occur on the timescale of immune signaling. And it explains why I and others who experienced an effect from the malic acid all described being able to avoid PEM (despite this detail not being shared between us ahead of time).
Added: There is also probably an additional piece of CNS involvement, which I can only speculate about, having to do with neurological sensing of mitochondrial NADH capacity resulting in the feeling of fatigue. I'm thinking that there might be a perfectly rational biological explanation for that "reduced activity motivation" that the BPS crowd loves to harp on about.
