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

Discussion in 'ME/CFS research' started by John Mac, Sep 4, 2019.

  1. leokitten

    leokitten Senior Member (Voting Rights)

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    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.
     
    Last edited: Feb 28, 2020
  2. leokitten

    leokitten Senior Member (Voting Rights)

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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.


     
    Last edited by a moderator: Feb 28, 2020
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  3. leokitten

    leokitten Senior Member (Voting Rights)

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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?
     
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  4. leokitten

    leokitten Senior Member (Voting Rights)

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    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.
     
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  5. ScottTriGuy

    ScottTriGuy Senior Member (Voting Rights)

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    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/
     
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  6. leokitten

    leokitten Senior Member (Voting Rights)

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    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?
     
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  7. ScottTriGuy

    ScottTriGuy Senior Member (Voting Rights)

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    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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  8. Sly Saint

    Sly Saint Senior Member (Voting Rights)

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    Last edited by a moderator: Oct 2, 2021
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