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New Exercise Study Brings Both Illumination and Questions
Simon McGrath looks at new objective evidence of abnormal response to exercise in ME/CFS patients, and the questions that researchers are still trying to answer ...
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new Alan Light paper... alpa-2a, glutocorticoid implication

Discussion in 'Latest ME/CFS Research' started by voner, Oct 8, 2013.

  1. voner

    voner Senior Member

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    Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression

    Jacob D. Meyerab, Alan R. Lightc, Sanjay K. Shuklad, Derek Clevidencee, Steven Yaled, Aaron J. Stegnerb & Dane B. Cookab*
    [...]

    Fatigue: Biomedicine, Health & Behavior
    Available online: 02 Oct 2013
    DOI: 10.1080/21641846.2013.838444
    ABSTRACT
    Background: A primary complaint of chronic fatigue syndrome (CFS) patients is post-exertion malaise, which is a worsening of symptoms following activities such as exercise. Purpose: To examine the link between gene expression for metabolite, adrenergic, immune, and glucocorticoid receptors on leukocytes and symptoms (pain, fatigue, and mood) following a maximal exercise test. Methods: Thirteen CFS patients and 11 healthy participants matched on age and fitness underwent blood draws and completed questionnaires immediately before, and 15 minutes, 48 hours, and 72 hours following, maximal exercise. Symptom and genetic measures collected before and after exercise were compared using a doubly multivariate repeated-measures analysis of variance. Results: This comparison of CFS and healthy participants resulted in a significant multivariate main effect for Group (p < 0.05). Univariate analyses indicated group differences for adrenergic α-2A and glucocorticoid (NR3C1) receptor messenger ribonucleic acid and symptoms of fatigue and confusion. Changes in gene expression were significantly correlated with symptoms. Conclusions: Results suggest that increased glucocorticoid sensitivity may contribute to the symptoms of post-exertion malaise in CFS. As NR3C1 interacts with other transcription factors, investigating the resulting cascades may lead to greater understanding of the biological mechanism of post-exertion malaise. This finding, if confirmed, could lead to novel approaches to prevent symptom exacerbation in CFS.

    Keywords: chronic fatigueexercisegenomicsmetabolitepost-exertion malaisepsychobiology

    http://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444

    here is a summary, you will need to put the webpage into google translate....

    http://www.hetalternatief.org/Inspanning Genexpressie GR Light 2013 1171.htm

    http://translate.google.com/transla...pression&client=safari&hl=en&biw=1024&bih=672
  2. lansbergen

    lansbergen Senior Member

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    Remember this? http://www.ncbi.nlm.nih.gov/pubmed/11585638
    LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone.
  3. Valentijn

    Valentijn Activity Level: 3

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    Interesting ... a pretty rare homozygous NR3C1 turned up in my 23andMe results when I ran them through our rare allele download at rs10515522. I'm homozygous as CC, which should have a prevalence rate of about 0.5%
  4. alex3619

    alex3619 Senior Member

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    Grumble, grumble, paywall. I have a biochemical interest in both LPS related responses, and the glucocorticoid issue.

    As a personal comment, I seem to get exaggerated and severe reactions to adrenaline.

    There may also be links to eicosanoid modulation that are important, a topic I have been interested in for 20 years now.
    Delia and Valentijn like this.
  5. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    OK, it's morning so brain not yet up to speed, but on the face of it I am puzzled by 'increased glucocorticoid sensitivity'. Would that not reduce inflammation, immune activity and pain - the opposite of what happens? Or is this particular glucocorticoid receptor involved in something else? So I did a brief search for 'NR3C1' and got this page. The Wikipedia link is very detailed. Any thoughts?

    To me this receptor seems to have such a baffling variety of functions that I can't begin to get my head round it.

    Perhaps in the end it is just one of the things that is attacked by autoantibodies, although being part of the stress hormone system it could be part of a perpetuating loop.
  6. Snow Leopard

    Snow Leopard Senior Member

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    See also this paper from Light and team, published last month:
    http://forums.phoenixrising.me/inde...ssion-profiles-associated-with-fatigue.25486/

    This makes sense, when considering the IL-10 results too.

    See also:
    http://en.wikipedia.org/wiki/Glucocorticoid_receptor

    A previous study on pediatric CFS found downregulated NR3C1 at baseline. It will be interesting to see if these post-exercise findings can be replicated.

    Possible Genetic Dysregulation in Pediatric CFS
    Author(s)
    Leonard A. Jason, Matthew Sorenson, Nicole Porter, Molly Brown, Athena Lerch, Constance Van der Eb, Judy Mikovits
    http://www.scirp.org/Journal/PaperInformation.aspx?paperID=3046


    In any event, the strong upregulation of adrenergic receptors post-exercise is rather interesting, we need to look at what regulates the expression of these genes and why.

    But I cannot help but think it is a response to severe fatigue, rather than the cause of it. I wonder about the gene expression of normal controls once they have exercised themselves to the level of exhaustion of patients and need to rely on an elevated adrenergic response just to function, along with an exaggerated anti-inflammatory response to minimise oxidative stress etc.
    Either that or there is a strange loop going on here which does not fit the current (normative) neuroendocrine model.
    anne_likes_red, Valentijn and MeSci like this.
  7. Snow Leopard

    Snow Leopard Senior Member

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    Following up,
    "Regulation of Glucocorticoid Receptor Activity by a Stress Responsive Transcriptional Cofactor"
    http://mend.endojournals.org/content/25/1/58.abstract

    anne_likes_red likes this.
  8. Snow Leopard

    Snow Leopard Senior Member

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    anne_likes_red and Valentijn like this.
  9. lansbergen

    lansbergen Senior Member

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    I know for a long time something is wrong with the cortico system. In infected animals dexamethasone had a opposite effect of what one would exect. It made the problem worse. The first time I mentioned it they thought I was crazy.
  10. Snow Leopard

    Snow Leopard Senior Member

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    The thing is, none of the findings so far actually explain it. Any potential reason/cause for this is outside of what has been researched in CFS so far.

    I'm wondering if anyone has made a comprehensive map of the (normal) neuroendocrine system and many downstream variables (I'd like to see a model/map with at least 25 variables)?
  11. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    I'm certain of it. I doubt that many people here would disagree. Figuring out what is wrong, why, and how to fix it, are not so easy.
  12. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Ah - so the receptor is upregulated because more anti-inflammatory action is needed, but it can't upregulate enough to exert adequate action, maybe because the demand is so abnormally great.

    Yes, I would agree that it is probably a response to, rather than a cause of, fatigue - at least immediate fatigue. I wonder what levels are like when PEM kicks in.

    Yes, a study like that on controls would be interesting.
  13. Gijs

    Gijs Senior Member

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    We see that the stress system kicks in when we physically exert ourselves. This is an abnormal response. Is this to compensate? lack of energy. Or is this purely an exaggerated action of our stress system. Shoot a mosquito with a gun, why?
  14. Snow Leopard

    Snow Leopard Senior Member

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    There have been two post-exercise studies that showed normal cortisol responses compared to controls (one study explicitly used sedentary controls)

    http://www.karger.com/Article/FullText/54863
    http://www.psychosomaticmedicine.org/content/64/6/951.long

    Both reported a slight decrease in ACTH, perhaps due to slight increases in ACTH receptor expression in response to exercise. (the melanocortin receptor 2 itself has its own roles and melanocortin receptor expression increases in response to exercise)

    I would actually say that so far it seems the endocrine stress-response still seems remarkably robust in CFS patients. To me the patterns found suggest are likely due to factors outside this immediate system.

    Side note:

    Decent introduction to the Endocrine system, it will take me a while to study this one though...
    http://www.ncbi.nlm.nih.gov/books/NBK20/
  15. Valentijn

    Valentijn Activity Level: 3

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    Is it possible that the up-regulation after exertion is resulting in the receptors getting worn out and under-performing at other times?
  16. Snow Leopard

    Snow Leopard Senior Member

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    I don't quite understand what you mean as the receptors either work unless they are antagonised by other enzymes or degraded by other chemical processes. Besides that, receptor affinity can be altered by SNP mutations and there have been some evidence of SNPs for GR DNA sequences in some patients, but the results were not overwhelming to me (did not have high sensitivity or specificity).

    GR density or affinity have been tested and found to be in the normal range.

    In general, an enzyme and its receptor(s) are in dynamic equilibrium and expression should shift based on stimulus outside of the immediate system, which is what we see here.

    Perhaps what you mean is could there be a larger dynamic range (greater highs and lows) in receptor expression or function? Maybe, that is an interesting question but it cannot be answered so far.

    The most likely consequence, perhaps is for the GR to remain slightly above normal levels and glucocorticoids to be as slightly below normal levels.

    Keeping in mind that cortisol's primary and original function was not part of the stress system, but to aid in glucose metabolism. In my opinion cortisol levels are slightly low due to the function of the liver which has its own regulatory system and can suppress cortisol through reduction of vasopressin. (although this can also have the consequences of stimulating orthostatic intolerance)

    The question is why would we see this sort of balance when not facing physical stress and why do we see increased responsivity when physical stress is faced?

    The main functions of the GR are transactivation, and transrepression.
    http://en.wikipedia.org/wiki/Glucocorticoid_receptor

    The shift towards transrepression must mean something in my opinion. This is in some ways a more direct way to repress the immune system through complexing with NF-κB or AP-1 and preventing the resulting gene expression.

    NF-κB aka (nuclear factor kappa-light-chain-enhancer of activated B cells) is interesting as that it is involved in a range of immunological responses to infection, inflammatory cytokines, and other chemicals, of particular note reactive oxygen or nitrogen species. It it is involved in stimulating both adaptive and innate immune system responses, but as usual in biochemistry, it is also involved with a whole bunch of other stuff.

    If there are immunological loops involved, NF-κB is likely to be involved and it is already implicated in autoimmune disorders and b-cell lymphomas.

    NF-κB has been shown to have increased expression in the Kerr studies, and activity in a Maes study, perhaps others.

    What is interesting to me is the potential for NF-κB dysregulation when faced with oxidative stress and continued levels of reactive oxygen or nitrogen species. Some of this has already been discussed in the literature. (from some of the well known researchers)
    But if the NF-κB is stimulating events that is causing the increased oxidative stress, then you have an autoimmune loop.

    Perhaps the HPA axis is simply responding to this overall picture and is not, in itself dysfunctional. Further, perhaps some patients who suffer increased severity, particularly post-exertional severity may have a lower response of GR receptor expression.
    alex3619 and Valentijn like this.
  17. lansbergen

    lansbergen Senior Member

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    Yep
  18. Valentijn

    Valentijn Activity Level: 3

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    I've read the full paper now, and it looks like they did a really good job of controlling for various variables, though it is a small study (13 patients, 11 controls) and uses Fukuda (any boldings and typos are mine):
    I'm impressed that they managed to control for fitness levels, which presents a pretty strong argument against any changes being due to deconditioning. They also took a close look at all of the peak exercise data, and the only significant difference was in perceived pain - hence both groups were performing similarly to each other.

    All of the mRNA measures were the same at baseline, but AD2A was about 3 times higher immediately after exertion in patients versus controls, and about 2 times higher at 48 and 72 hours. NR3C1 was 1.6 times higher immediately after exertion, 2.28 times higher at 48 hours, and 1.39 times higher after 72 hours. IL-10 and P2X4 were about the same for patients versus controls at all times.

    The also found correlation between PEM symptoms gene expression, which might be suggesting that either upregulation could be causing the symptoms, or that a common factor is causing both the upregulation and the symptoms:
    And their speculation on why this is happening:
    So basically it seems like the biggest immediate effect is rising AD2A (3x higher than controls), which is followed by NR3C1 expression peaking two days later. What I'm not clear on is whether the NR3C1 rise is triggered by the AD21 rise, or both are triggered by a separate mechanism.

    Does the AD2A cause the abnormal inflammation itself? Is the NR3C1 increasing to cope with that? And if AD2A or NR3C1 are hurting more than they're helping, is there a way to stop them from over-expressing?
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  19. Valentijn

    Valentijn Activity Level: 3

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    This paper also contained a brief discussion of other research into NR3C1 in CFS, from a genomic standpoint:
    Oddly, it's the major alleles of those SNPs which are more associated with risk (I'm homozygous for all of the minor alleles, which is pretty rare). And none of them are listed as missense mutations, which is rather confusing. But it looks like Unger is involved in that study, so it's probably got a bunch of non-ME patients.

    And one of the studies claims to attribute genes to 76% of the risk of getting CFS, which seems a bit unlikely. I need to take a closer look at all three of the studies cited:
  20. lansbergen

    lansbergen Senior Member

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    Valentijn likes this.

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