"They found that rapamycin lowers mitochondrial respiration and induces a shift from OXPHOS towards glycolysis as measured by metabolic profiling."
http://rsob.royalsocietypublishing.org/content/3/12/130185
That's very interesting. But the paper does say just before the sentence you quoted that:
Ramanathan & Schreiber [64] used a shorter rapamycin treatment to exclude transcriptional effects.
The "transcriptional effects" refers to rapamycin's alteration mitochondrial gene expression, and I think what they are saying is that in a study using a short rapamycin treatment, you can measure the initial effects of rapamycin on the mitochondria before this drug later starts altering mitochondrial gene expression.
It appears from the paper you quoted that the initial effect of rapamycin is to
reduce mitochondrial respiration (mitochondrial aerobic energy output), and this effect is caused by rapamycin's down-regulation of mTORC1. The paper explains it:
Blocking mTORC1 by a 12-h rapamycin treatment lowers Δψm and maximal oxidative capacity
Δψm is the voltage across the mitochondrial membrane, analogous to the voltage of a battery. So the initial short term effect (in the first 12 hours) of rapamycin's inhibition of mTORC1 is a
reduction in mitochondrial aerobic energy output, which would likley be undesirable in ME/CFS.
However, in the longer term (judging by the results of the
paper I mentioned earlier), as rapamycin starts altering mitochondrial gene transcriptional, this drug would appear to provide a net
increase in mitochondrial aerobic energy output, in spite of the fact that rapamycin's mTORC1 inhibition reduces the energy output.
So my guess is that rapamycin may have two opposing effects on mitochondrial respiration: an initial reduction in aerobic energy output caused by mTORC1 inhibition, and a later increase in aerobic energy output due to alterations in mitochondrial gene expression. And I think it is the latter effect that dominates in the long term, providing an overall increase in aerobic energy output.
This echos
@nandixon's comment earlier in the thread:
So either rapamycin must be doing something else that beneficially offsets that seeming disaster, or diversion of pyruvate away from the mitochondria is actually beneficial in ME/CFS.
Anyway, that's my interpretation, but I could be wrong, because it's hard to understand these papers. It could explain, though, why I felt more tired and brain fogged the for two days after taking rapamycin, before some glimmers of benefits kicked in at around day three.
)
