The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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Identification of ME/CFS-associated DNA methylation patterns.

Discussion in 'Latest ME/CFS Research' started by Murph, Jul 24, 2018.

  1. Murph

    Murph :)

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    PLoS One. 2018 Jul 23;13(7):e0201066. doi: 10.1371/journal.pone.0201066. eCollection 2018.
    Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns.
    Trivedi MS1, Oltra E2, Sarria L3, Rose N1, Beljanski V4, Fletcher MA3,5, Klimas NG3,5, Nathanson L3.
    Author information
    Abstract

    BACKGROUND:
    Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition involving multiple organ systems and characterized by persistent/relapsing debilitating fatigue, immune dysfunction, neurological problems, and other symptoms not curable for at least 6 months. Disruption of DNA methylation patterns has been tied to various immune and neurological diseases; however, its status in ME/CFS remains uncertain. Our study aimed at identifying changes in the DNA methylation patterns that associate with ME/CFS.

    METHODS:
    We extracted genomic DNA from peripheral blood mononuclear cells from 13 ME/CFS study subjects and 12 healthy controls and measured global DNA methylation by ELISA-like method and site-specific methylation status using Illumina MethylationEPIC microarrays. Pyrosequencing validation included 33 ME/CFS cases and 31 controls from two geographically distant cohorts.

    RESULTS:
    Global DNA methylation levels of ME/CFS cases were similar to those of controls. However, microarray-based approach allowed detection of 17,296 differentially methylated CpG sites in 6,368 genes across regulatory elements and within coding regions of genes. Analysis of DNA methylation in promoter regions revealed 307 differentially methylated promoters. Ingenuity pathway analysis indicated that genes associated with differentially methylated promoters participated in at least 15 different pathways mostly related to cell signaling with a strong immune component.

    CONCLUSIONS:
    This is the first study that has explored genome-wide epigenetic changes associated with ME/CFS using the advanced Illumina MethylationEPIC microarrays covering about 850,000 CpG sites in two geographically distant cohorts of ME/CFS cases and matched controls. Our results are aligned with previous studies that indicate a dysregulation of the immune system in ME/CFS. They also suggest a potential role of epigenetic de-regulation in the pathobiology of ME/CFS. We propose screening of larger cohorts of ME/CFS cases to determine the external validity of these epigenetic changes in order to implement them as possible diagnostic markers in clinical setting.

    PMID:
    30036399
    DOI:
    10.1371/journal.pone.0201066
    DOI:
    10.1016/j.nicl.2018.04.025
    https://www.ncbi.nlm.nih.gov/pubmed/30036399
     
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  2. Murph

    Murph :)

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    1. Here's the top genes they found that were wonky. Top one is p38 Mapk, which I had not heard of, but is involved in responding to cytokines.
    2. Not surprised to see IL-10 (inflammation marker) and AMPK (metabolism controller) in the next two spots.

    journal.pone.0201066.g006.PNG

    We don't know if these genetic adaptation are a cause or an effect, as they explain here:

     
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  3. RWP (Rest without Peace)

    RWP (Rest without Peace) Senior Member

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    @Murph

    Beyond these comments, can you help us with "what's the significance" or "what this could lead to"?

    Thanks,

    RWP
     
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  4. Murph

    Murph :)

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    I wish!

    At a very high level the main immediate benefit is this research helps further establish me/cfs as a physical condition, and highlghts that the issues are in the immune and metabolic systems.

    I see this as more of a high level survey expedition to see where deserves more exploration . I expect those p38 MAPK pathways deserve more attention and I hope these guys will give it.
     
  5. RWP (Rest without Peace)

    RWP (Rest without Peace) Senior Member

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    @Murph

    Thanks for explaining!
     
  6. panckage

    panckage Senior Member

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    This looks like an observation based study (as opposed to hypothesis based) that Ron Davis has been so desperately trying to get funds for
     
  7. AdamS

    AdamS Senior Member

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    Thanks for posting @Murph

    IL17 showing up quite a lot huh! Seems to be broadly associated with quite a number of autoimmune diseases, could be a good theraputic target!
     
  8. Murph

    Murph :)

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    Agree this is observation based. It will hopefully allow some good hypotheses to be formulated and then tested!
     
  9. Murph

    Murph :)

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    Very curiously I just came across the p38 MAPK (the genetic pathway that looks most wonky in this study) again!

    I was doing some reading on how best to organise a keto diet after seeing this intriguing thread by @leokitten

    https://forums.phoenixrising.me/index.php?threads/first-time-in-remission-with-ketogenic-diet.60886/

    My reading had me trying to figure out the right ratios of protein and fat you need to stay in ketosis. The question seems to be which of those nutrients causes the body to produce more endogenous glucose in the liver (gluconeogenesis). Some think that if you eat a lot of protein you will get enough blood glucose to stop being in ketosis. Others disagree. (I have no dog in that fight.)

    Anyway one of the top results I found on gluconeogenesis is this, and I clicked on it because it involves my favourite of all the kinases, AMPK. (AMPK keeps popping up in this disease and I'm sure it's disturbed in some way)

    This is an especially interesting paper, I thought, because it involves the liver, a topic which @mariovitali is reliable in bringing to our attention.

    Unfortunately the biochemistry is pretty complex but the key points I take away are that:
    • dodgy p38 MAPK pathways can impair energy function, and
    • p38 MAPK is involved in a couple of things that we're already moderately confident are relevant to ME/CFS, namely, AMPK, keto diets, and the liver.
    p38 MAPK is getting a lot of attention as a target in a range of diseases but it could be its metabolic role that is important to us.

    J Hepatol. 2015 Jun;62(6):1319-27. doi: 10.1016/j.jhep.2014.12.032. Epub 2015 Jan 13.
    Hepatic p38α regulates gluconeogenesis by suppressing AMPK.
    Jing Y1, Liu W1, Cao H2, Zhang D2, Yao X2, Zhang S2, Xia H2, Li D3, Wang YC4, Yan J5, Hui L3, Ying H6.
    Author information
    Abstract

    BACKGROUND & AIMS:
    It is proposed that p38 is involved in gluconeogenesis, however, the genetic evidence is lacking and precise mechanisms remain poorly understood. We sought to delineate the role of hepatic p38α in gluconeogenesis during fasting by applying a loss-of-function genetic approach.

    METHODS:
    We examined fasting glucose levels, performed pyruvate tolerance test, imaged G6Pase promoter activity, as well as determined the expression of gluconeogenic genes in mice with a targeted deletion of p38α in liver. Results were confirmed both in vivo and in vitro by using an adenoviral dominant-negative form of p38α (p38α-AF) and the constitutively active mitogen-activated protein kinase 6, respectively. Adenoviral dominant-negative form of AMP-activated protein kinase α (DN-AMPKα) was employed to test our proposed model.

    RESULTS:
    Mice lacking hepatic p38α exhibited reduced fasting glucose level and impaired gluconeogenesis. Interestingly, hepatic deficiency of p38α did not result in an alteration in CREB phosphorylation, but led to an increase in AMPKα phosphorylation. Adenoviral DN-AMPKα could abolish the effect of p38α-AF on gluconeogenesis. Knockdown of up-steam transforming growth factor β-activated kinase 1 decreased the AMPKα phosphorylation induced by p38α-AF, suggesting a negative feedback loop. Consistently, inverse correlations between p38 and AMPKα phosphorylation were observed during fasting and in diabetic mouse models. Importantly, adenoviral p38α-AF treatment ameliorated hyperglycemia in diabetic mice.

    CONCLUSIONS:
    Our study provides evidence that hepatic p38α functions as a negative regulator of AMPK signaling in maintaining gluconeogenesis, dysregulation of this regulatory network contributes to unrestrained gluconeogenesis in diabetes, and hepatic p38α could be a drug target for hyperglycemia.
     
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  10. ljimbo423

    ljimbo423 Senior Member

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    This is a list of supplements and other inhibitors of P38 MAPK. On it are Ginsenoside Rg1 from Ginseng, L-theanine from green tea, Icarin from Horny Goat weed-(Yup that's a real supplement-:)), Apigenin from Chamomile tea, Astaxanthin and others.

    upload_2018-7-31_11-28-16.png

    LINK
     
  11. Murph

    Murph :)

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    Doing more reading. There's lots of evidence p38 MAPK is triggered by exercise. Which is a waaaay more mainstream and predictable reason for it being disturbed in ME/CFS than its association with cytokines or glucose metabolism or ketogenic diets!


    For example, these 2 studies:

    This study shows p38 MAPK can be activated in response to exercise, and it is supposed to turn on another thing (PGC1alpha) that (partially) controls glucose metabolism and the making of new mitochondria and muscle.


    PGC-1gene regulation in skeletal muscle (Akimoto, Pohnert, et al. 2005)


    PGC-1 promotes mitochondrial biogenesis and slow fiber formation in skeletal muscle. We hypothesized that activation of the p38 mitogen-activated protein kinase (MAPK) pathway in response to increased muscle activity stimulates PGC-1gene transcription as part of the mechanisms for skeletal muscle adaptation. Here we report that a single bout of voluntary running induces a transient increase of PGC-1mRNA expression in mouse plantaris muscle, concurrent with an activation of the p38 MAPK pathway.


    PGC-1, a transcriptional co-activator cloned from a differentiated brown fat cell line (3), has recently been identified as an important regulator of adaptive thermogenesis, glucose metabolism, mitochondrial biogenesis and muscle fiber type specialization (4). Several lines of evidence are consistent with the notion that PGC-1functions in promoting oxidative capacity in skeletal muscle. Firstly, overexpression of PGC-1in cultured myoblasts increases mitochondrial biogenesis and oxidative respiration (5), and muscle-specific overexpression of PGC-1in transgenic mice results in enhanced mitochondrial biogenesis and more slow-twitch (type I) fiber formation (6). Secondly, endurance exercise induces PGC-1mRNA and protein expression in rats and humans).
    -----

    This study finds similar: p38 MAPK is turned on by intense workouts. It is meant to help you adapt to exercise. (I wonder what ways it can go wrong.)

    Gibala MJ, McGee SL, Garnham AP, Howlett KF, Snow RJ, Hargreaves M.
    Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1in human skeletal muscle.
    J Appl Physiol 106: 929–934, 2009. First published December 26, 2008; doi:10.1152/japplphysiol.90880.2008.—

    From a cell signaling perspective, short-duration intense muscular work is typi- cally associated with resistance training and linked to pathways that stimulate growth. However, brief repeated sessions of sprint or high- intensity interval exercise induce rapid phenotypic changes that re- semble traditional endurance training. We tested the hypothesis that an acute session of intense intermittent cycle exercise would activate signaling cascades linked to mitochondrial biogenesis in human skel- etal muscle. Biopsies (vastus lateralis) were obtained from six young men who performed four 30-s “all out” exercise bouts interspersed with 4 min of rest (80 kJ total work). Phosphorylation of AMP- activated protein kinase (AMPK; subunits 1 and 2) and the p38 mitogen-activated protein kinase (MAPK) was higher (P 0.05) immediately after bout 4 vs. preexercise. ... We conclude that signaling through AMPK and p38 MAPK to PGC-1may explain in part the metabolic remodeling induced by low-volume intense interval exercise, includ- ing mitochondrial biogenesis and an increased capacity for glucose and fatty acid oxidation.
     
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  12. Murph

    Murph :)

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    My excitement about p38 MAPK has peaked and is now cooling.

    The more I look the more p38MAPK starts to look like one of those everywhere enzymes. Does cool stuff no matter where it is in the body. e.g.

    p38α MAPK is required for tooth morphogenesis and enamel secretion.

    Greenblatt MB, Kim JM, Oh H, Park KH, Choo MK, Sano Y, Tye CE, Skobe Z, Davis RJ, Park JM, Bei M, Glimcher LH, Shim JH. J Biol Chem. 2015 Jan 2;290(1):

    So ... who knows how informative it is that this pathway is out of whack in us...
     
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  13. AdamS

    AdamS Senior Member

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    Either way, many thanks for exploring it further, I don’t have the brain power at the minute but I do remember p38 MAPK being referenced in relation to NK cell dysfunction in ME/CFS a while back and given its prominence in this study it certainly seems important.
     
  14. Belbyr

    Belbyr

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    Could you help break this down into 5th grader terms?

    I have CFS and can tell weight lifting can increase CFS symptoms for the next 1-2 days. I know I need exercise because I also have mild POTS, so my legs need pumping and strength. Is there something I can do to lower the 'gassed' symptoms?
     
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  15. wastwater

    wastwater Senior Member

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    I've heard of p38 in relation to glaucoma and teeth (microdontia) also heard of CREB(cAMP)
     
  16. Snow Leopard

    Snow Leopard Hibernating

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    This study is the most interesting of all of the studies published in July.

    p38 MAPK pathway disregulation is likely to be a (nonspecific) marker of fatigue. I have discussed this previously with reference to the following studies:

    "Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue" (2011)

    Which likely influenced the following study.

    "Meta analysis of Chronic Fatigue Syndrome through integration of clinical, gene expression, SNP and proteomic data" (2012)

    The actual mechanism of the association with fatigue remains unknown. There are drugs (intended to be anti-cancer therapies, because that is where much drug development is focused) with directly target P38 MAPK and don't necessarily cause severe fatigue directly. P38 MAPK is a key downstream target of many cellular sensory functions and therefore has had a lot of attention when it comes to trying to understand cellular senescence/aging processes and tumor growth.

    Several years ago I also tried to formulate hypotheses to explain why certain Receptor Tyrosine Kinases (also trialed or used as anti-cancer drugs) induce severe fatigue in many patients. Looking at the MAPK cascades was an obvious place to start. Unfortunately I didn't come up with anything that would be more convincing than the typical hypothesis you read in the Medical Hypotheses journal (I'm usually not too impressed with that journal), there is still too much we don't know.

    Anyway, a key point to stress is that the dysregulation of MAPK pathways is likely downstream and while this is a sign something is not right, these are not the pathways to target either as a highly specific biomarker or as a therapeutic target. My primary hypothesis still proposes that the signals that cells are responding to are ultimately extracellular and hence why I have spent much time looking at RTKs and GPCRs, rather than downstream processes. Metaboreceptors for example are of particular interest to me and this is also why the Lights (and colleagues) have been looking at GPCR gene expression post-exercise for example (actually their hypothesis proposes a combination of receptors that must be activated for a fatigue signal.)

    note: RTK and GPCR activation of MAPKs:
    http://www.epitomics.com/products/pathways/MAPKp38.php
    https://en.wikipedia.org/wiki/MAPK/ERK_pathway
    http://pathwaymaps.com/maps/455 (GPCR)
     
    Last edited: Aug 10, 2018
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