@DMissa In the years that have passed since this paper was published did you get any good feedback on mtor in ME/CFS?
Mtor/rapamycin seems to be really hyped right now but with very little quality data, and when I asked around in 2019 I got the impression that unpublished work did not indicate any difference in mtor in ME/CFS. Many people must have looked at this as it is a fairly obvious thing to study in a disease with reduced energy.
Have you been able to determine if the mtor effect is specific to LCL's vs elsewhere in the body? I understand if it's work in progress and you can't comment.
You have kind of spear gunned the elephant in the room here. It's been a bit of a source of puzzlement for me to see, in some cases, pathway-specific biology applied to disease models without a heap of specific tissue or cell type rationale or little reference to current genetic evidence. It is common to see it said that "X pathway is up or down" which I think is hard to explain as systemic without an
overt genetic issue affecting one of the key gene products - and I think we would have identified this by now were it the case. I think it is more likely that combinations of interacting but more subtle factors are at play. Some may be genetic in basis and decodeME will help us nail this down.
I don't want to speak about specific results before published but the work we have done (including other tissues) leaves me unconvinced that there is a
systemic mTORC1 issue. I am confident that what we are seeing wrong is specifically part of abnormal metabolism in particular immune subsets, in this case B cells. In terms of plausibility, lupus and MS (particularly EAE model) feature elevated mTORC1 activity in B cells as well so there is precedent for its activity being shifted in diseases with
some overlapping characteristics. In terms of how mTORC1 in LCLs relates to other metabolic shifts that we have seen, we have a PhD student working on this.
Whether metabolic shifts arise from other issues in signalling and whether they are contributing to eg: aberrant effector function... we don't know, and this is where I strongly believe that more understanding of the fundamental biology is going to play an important part. I am putting together ideas for grants that will be "basic science" to look at these or related mechanisms (not specifically in an ME/CFS context) but the knowledge gain will flow on to help us understand the connections between these things.
Basically think of it as a spider web. If you pluck any particular "node" on it you might see a ripple across the whole web, but the important thing to determine is not which parts of the web are wobbling (most of them probably are by definition; biology is so interconnected and something like mTORC1 is incredibly central to signalling) - it's to find out what's being plucked, and if the other parts that are wobbling cause other consequences relevant to the syndrome or are just funny to look at. In the LCL spiderweb we are seeing mTORC1 wobbling but we don't know where the pluck happened or what the particular effects relevant to the syndrome are. We're working on answering this