An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients Missailidis et al. 2019

I also just thought of a potential connection to these research results and why rituximab works in an ME subgroup.

mTOR activity also regulates immune responses and microenvironment in addition to cell cycle and metabolism. Increased mTOR activity will activate B cells via IL-2 (as well as other immune cell types).

So, given that these results show mTOR is chronically hyperactivated in ME lymphocytes, then maybe in some ME patients mTOR -> IL-2 -> B cell activation is an important driver of symptoms and killing B cells with rituximab works.
 
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Regulation of Immune Responses by mTOR

Abstract
mTOR is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental cues in the form of growth factors, amino acids, and energy. In the study of the immune system, mTOR is emerging as a critical regulator of immune function because of its role in sensing and integrating cues from the immune microenvironment. With the greater appreciation of cellular metabolism as an important regulator of immune cell function, mTOR is proving to be a vital link between immune function and metabolism.

In this review, we discuss the ability of mTOR to direct the adaptive immune response. Specifically, we focus on the role of mTOR in promoting differentiation, activation, and function in T cells, B cells, and antigen-presenting cells.

 
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ScottTriGuy said:
Fwiw, I am a responder to Rapamune / Rapamycin, an mTOR inhibitor.
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This is very interesting, for me the only treatments that ever worked and helped with symptoms are fasting and ketogenic diet. Every other treatment ever mentioned here (or on PR) or my ME specialist recommended that I tried never did anything, not even any placebo effect.

If you read in this paper though they describe that increased mTOR activity is part of a stress response to ATP synthase inefficiency and lower ATP levels in the ME cell relative to OCR.

They also used Torin1 (an mTOR inhibitor like sirolimus/rapamycin/rapamune) and saw the cells increased the same stress response even more.

So I wonder if taking rapamycin might improve symptoms because it would reduce the side effects mTOR hyperactivity (immune activation, inflammation, possible viral reactivation, etc.) even though it seems to be inhibiting the cell’s response trying to get ATP levels back up?

mTOR isn’t the only nutrient- and stress-sensing protein controlling cellular activity at the crossroads of these cell signaling pathways. There’s also AMPK and HBP, and the relationship is quite complex so it could be mTOR inhibition helps because the cells use alternative signaling pathways to increase ATP production in ME lymphocytes.

What was your rapamycin dosage and frequency? How long did you take it for?
 
Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling

Abstract
O-linked N-acetylglucosamine, better known as O-GlcNAc, is a sugar post-translational modification participating in a diverse range of cell functions. Disruptions in the cycling of O-GlcNAc mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively, is a driving force for aberrant cell signaling in disease pathologies, such as diabetes, obesity, Alzheimer's disease, and cancer. Production of UDP-GlcNAc, the metabolic substrate for OGT, by the Hexosamine Biosynthetic Pathway (HBP) is controlled by the input of amino acids, fats, and nucleic acids, making O-GlcNAc a key nutrient-sensor for fluctuations in these macromolecules. The mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways also participate in nutrient-sensing as a means of controlling cell activity and are significant factors in a variety of pathologies. Research into the individual nutrient-sensitivities of the HBP, AMPK, and mTOR pathways has revealed a complex regulatory dynamic, where their unique responses to macromolecule levels coordinate cell behavior. Importantly, cross-talk between these pathways fine-tunes the cellular response to nutrients. Strong evidence demonstrates that AMPK negatively regulates the mTOR pathway, but O-GlcNAcylation of AMPK lowers enzymatic activity and promotes growth. On the other hand, AMPK can phosphorylate OGT leading to changes in OGT function. Complex sets of interactions between the HBP, AMPK, and mTOR pathways integrate nutritional signals to respond to changes in the environment. In particular, examining these relationships using systems biology approaches might prove a useful method of exploring the complex nature of cell signaling. Overall, understanding the complex interactions of these nutrient pathways will provide novel mechanistic information into how nutrients influence health and disease.
 
leokitten said:
What was your rapamycin dosage and frequency? How long did you take it for?
Click to expand...

I started in November 2018 and continue to take it. Initially at 1mg / day at breakfast (with fat to increase absorption) - but in the last year I done as little as every 3rd day for a few months - currently moving to a Mon - Wed - Fri schedule.

David Sabatini is the go-to guy for mTor research --there is a good interview with him about rapamycin on the Peter Attia podcast: https://peterattiamd.com/davidsabatini/
 
ScottTriGuy said:
I started in November 2018 and continue to take it. Initially at 1mg / day at breakfast (with fat to increase absorption) - but in the last year I done as little as every 3rd day for a few months - currently moving to a Mon - Wed - Fri schedule.
Click to expand...

With 1mg / 3 days have you and your doctor seen any of the obvious side effects? i.e. metabolic: hyperglycemia, hyperlipidemia, hypertriglyceridemia or immunosuppression: increased infections, etc? EDIT: Any other side effects from long-term use?

Could you quantify as best you can how much it's improved your ME?
 
leokitten said:
With 1mg / 3 days have you and your doctor seen any of the obvious side effects? i.e. metabolic: hyperglycemia, hyperlipidemia, hypertriglyceridemia or immunosuppression: increased infections, etc? EDIT: Any other side effects from long-term use?

Could you quantify as best you can how much it's improved your ME?
Click to expand...

I've not noted any side effects -- pre-rapamune my max walking capacity on flat ground was 15 minutes -- about a month later I could do 30 - 40 minutes, so about doubled my exertion window -- I also noted that PEM was harder to induce, and the symptoms were less intense and shorter lived.
 
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forestglip said:
Relevant case report:

S4ME thread: mtDNA deletion m.8753_16566 with < 10 % heteroplasmy in muscle and isolated complex-V dysfunction misinterpreted as chronic fatigue syndrome over 21-years (2025, Clinics)
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we have a PhD student who is characterising cell lines from people with mutations to genes encoding complex V subunits, and who is also introducing complex v impairment into healthy control cell lines or introducing complex V mutations to model organisms and then phenotyping all of these as well - I will send this paper to him
 
@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.
 
wigglethemouse said:
@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.
Click to expand...
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
 
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