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Is this the mechanism underlying PEM?

Discussion in 'Post-Exertional Malaise, Fatigue, and Crashes' started by Woolie, Dec 2, 2017.

  1. Woolie

    Woolie Senior Member (Voting Rights)

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    Just came across this study that looks at the relationship between exercise and inflammation. Interesting for our purposes was that there is an increase in the levels of a whole host of inflammatory cytokines immediately after strenuous exercise.

    It occurred to me that in PwMEs, these inflammatory responses might be greatly exaggerated, leading to the experience of PEM.

    (this might not be news to some of you, but it was to me).

    Paper: Muscle-derived interleukin-6:mechanisms for activation and possible biological roles.
    respnse to exercise.jpg
    (figure is from this article: https://www.sciencedirect.com/science/article/pii/S0735109705004705#bib21)
     
  2. Alvin

    Alvin Senior Member (Voting Rights)

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    But PEM is often delayed, a day, two days, i once had a week delay (oy, that was a bad crash)
     
  3. Trish

    Trish Senior Member (Voting Rights)

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    This reminded me of Warren Tate's talk I watched recently,

    discussed here:
    https://www.s4me.info/index.php?thr...research-into-me-cfs-11th-november-2017.1271/

    At 31 minutes into the talk he shows graphs comparing healthy patients 24 hours after exercise cytokines decreasing, but ME patients 24 hours after exercise, most of the cytokines he measured increased. He thinks this is so significant it could be a biomarker.
     
  4. Woolie

    Woolie Senior Member (Voting Rights)

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    The time frame of the inflammation varies depending on the cytokine. But some cytokines don't peak till 24 hours later, and remain high for several days. That's mentioned in the article, although I forgot to explain it.
     
  5. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

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    Isn't PEM more about running out of ATP due to Krebs cycle inefficiency (whether from dysfunctional mitochondria or blocking agents at the cell membrane or both)?

    The inflammation markers could be a diagnostic or somehow regulatory, but I'm not sure how they explain the main PEM symptoms unless they turn off something to do with cellular energy production? It looks like they are saying that IL6 stimulates the production of more energy from glucose?

    I skim read but couldn't find how this would work as a therapy as they suggest if you don't have the ATP to be made in the first place.

    Not too hot cognitively today so would appreciate if someone has read it a brief explanation of what they are driving at other than its a marker for skeletal exercise. Sorry if I'm being thick but can't see it?
     
  6. MeSci

    MeSci Senior Member (Voting Rights)

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  7. Hip

    Hip Established Member (Voting Rights)

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    Huge amounts of IL-6 appear after exercise (100-fold increase in levels). However, IL-6 is a complex cytokine that has both pro-inflammatory and anti-inflammatory modes: the classical signaling IL-6 pathway is anti-inflammatory and instigates tissue repair, whereas the trans signaling IL-6 pathway is pro-inflammatory.

    When IL-6 is released by the muscles during exercise, it normally has an anti-inflammatory effect (classical signaling), and this may be one reason why exercise has beneficial effects (except of course in ME/CFS, when as is well-known, exercise typically makes you worse by triggering post-exertional malaise).

    I speculated that something may have gone wrong in ME/CFS, such that the IL-6 released during exercise now becomes pro-inflammatory (trans signaling) rather than anti-inflammatory (classical signaling), which might help explain why exercise usually causes ME/CFS to feel worse.

    So my hypothesis was that in ME/CFS, PEM might arise when the IL-6 released by exercise enters into the wrong pro-inflammatory pathway (trans signaling). My hypothesis is detailed in this post.

    IL-6 trans-signaling is also associated with cognitive dysfunction and neuroinflammation, so I thought that might explain how exercise can cause worsened brain fog in ME/CFS.

    Also, the timescale of IL-6 release from exercise corresponds well to the timescale of exercise-induced PEM: "exercise can increase IL-6 by up to sixfold at 5 hours post-exercise and threefold 8 days after exercise". Ref: 1 So all this elevated IL-6 after exercise might explain why PEM can last for several days or even weeks.



    The all-important factor that controls whether IL-6 enters into the pro-inflammatory (trans signaling) pathway rather than anti-inflammatory (classical signaling) pathway is the soluble IL-6 receptor, with the presence of this soluble IL-6 receptor causing IL-6 to enter into the trans signaling pathway.

    A soluble receptor is one which is not attached to any cellular membrane, but which floats around freely in the blood. So the more soluble IL-6 receptor there is in the blood, the more that IL-6 gets shunted into the the pro-inflammatory trans signaling pathway.

    So my hypothesis was that in ME/CFS, patients might have high levels of the soluble IL-6 receptor, which would explain why exercise has a bad effect in ME/CFS, but a good effect in healthy people.

    (Actually, it's slight more complicated, in that there is also a soluble gp130 receptor which inhibits IL-6 trans signaling; I will put the details of this in the following spoiler button — click on the button to view).

    IL-6 trans-signaling ➤ IL-6 binds to the soluble IL-6 receptor (sIL-6R) in the blood, and this combination of IL-6 + sIL-6R form a complex. This complex can then attach to and activate the glycoprotein 130 (gp130) receptor on cells. Ref: 1

    However, there is also a soluble version of gp130, called soluble gp130:

    Soluble gp130 (sgp130) inhibits the IL-6 trans-signaling pathway. Ref: 1

    Soluble gp130 acts as a partial antagonist, or decoy receptor, by binding the IL-6 + sIL-6R complex and preventing it from binding membrane-bound gp130 to initiate signal transduction. Ref: 1


    Unfortunately for my hypothesis, a study found that at rest as well as after exercise, there was no difference between ME/CFS patients and healthy controls in their levels of IL-6, their levels of the soluble IL-6 receptor, and their levels of the soluble gp130 receptor. So it looks from that study that IL-6 trans-signaling is not any higher in ME/CFS patients.
     
    Last edited: Dec 2, 2017
  8. Alvin

    Alvin Senior Member (Voting Rights)

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    Two reasonable theories. Personally i think both are wrong, As i explained PEM is often delayed and many things happen in our bodies that last day. I've been taking D Ribose to produce ATP which does seem to be part of the disease mechanism but i don't think is PEM since i still get it. That said i can't prove either theory wrong but neither has been correct either
    All that said i don't have a better theory to offer at the present time, i think more research will be needed to figure it out :emoji_fingers_crossed:
     
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  9. Barry

    Barry Senior Member (Voting Rights)

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    My wife takes D-Ribose and still gets PEM, but I don't think that means ATP deficit is automatically excluded from the PEM story. I'd be very surprised if orally taken D-Ribose magically fixes Krebs cycle problems.
     
  10. Woolie

    Woolie Senior Member (Voting Rights)

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    I think this would have an immediate effect, whereas some of the inflammation is delayed (24h to several days).
     
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  11. Woolie

    Woolie Senior Member (Voting Rights)

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    That's interesting, @Hip, thanks for posting.

    I wasn't thinking that any of the specific cytokines mentioned in the article are "responsible". As you say, that doesn't fit with the wide variability in cytokine profiles in PwMEs. I was thinking it pointed to inflammatory pathways in general.

    More like the Warrren Tate results in @Trish's post above.
     
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  12. Woolie

    Woolie Senior Member (Voting Rights)

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    I wasn't that interested in the topic of the paper (which was something about improving performance in athletes). Just the cytokine results.
     
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  13. Barry

    Barry Senior Member (Voting Rights)

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    But what if PEM is not the result of ATP depletion itself, but instead due to cumulative effects of ineffectually trying to replenish it? I've no medical knowledge, but it feels like there could be some payback effect of the body trying to recover from an extreme state, especially if the recovery mechanism were damaged in some way? Maybe that recovery mechanism is itself stressful for the body.
     
  14. lansbergen

    lansbergen Established Member (Voting Rights)

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    microdamage----->immune respomse?
     
  15. Barry

    Barry Senior Member (Voting Rights)

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    I don't know the veracity of this website, or even this article, but I'd be interested in the opinions of those with much better understanding than mine.

    http://www.medicalinsider.com/mitochondrial.html

     
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  16. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

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    The theory on D ribose is to reduce the period of PEM not prevent it or give you more energy.

    This is from memory and my dumbed down way of remembering it so may be faulty ...here goes feel free to correct etc:

    The theory says that normally you utilise ATP to ADP to release energy and then rephosphorylate ADP back to ATP and so on. This process is quick. In normal circumstances this is efficient.

    You also have a back up process when you run out of available ATP (running away from a predator or running a marathon etc) this is the release of energy from ADP to AMP. Problem then comes is that AMP can't be converted back to ADP since the process involves the destruction of the molecule. This means that you then have to create new ADP by the long process using new molecules of Ribose. Ribose takes ages to produce in the body from glucose and is not a process that can keep up with demand.

    The efficiency of how well you convert ADP back to ATP is your energy envelope.

    When you go over your energy envelope you will move out of equilibrium and start rapidly using up your ADP to AMP until you get to a tipping point when you need to replenish using ribose.

    Taking ribose will therefore speed this up. It won't improve the efficiency of ADP to ATP phosphorylation etc.
    So ribose is useful for people with ME since because we have stupidly low energy envelopes (due to some as yet unidentified inefficiency), we dip into our ADP-AMP option more frequently than healthy people. This is the reserve tank, and isn't ideal but may get you out of trouble. Relying on this mechanism is not sustainable. Taking ribose gets us back to normality quicker.

    It's possible that this theory could explain some sort of "resilience" to getting PEM but I think it's mainly about reducing the duration and severity.

    My personal view on this is that I think it may be part of the story but doesn't explain where the inefficiency starts and ends. It's highly possible that the mitochondria are dysfunctional from oxidants and this is a symptom rather than a core reason.

    I hope I've remembered all that right. As I said please feel free to correct...I'm cognitively challenged so didn't want to waste more energy re reading what I should already know.
     
  17. Barry

    Barry Senior Member (Voting Rights)

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    That's interesting, because I've had the feeling my wife's PEM that is less severe since taking D-Ribose, but just an impression nothing more.
     
  18. Woolie

    Woolie Senior Member (Voting Rights)

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    This ADP/ATP account seems to focus on the fatigue part of PEM. But many of us experience it more as an exacerbation of our symptoms, including general sick feeling, accompanied by neural symptoms, sore glands, etc.

    Yes, you could stretch the ADP/ATP account to all those other things, but in the process it would probably lose everything that makes it currently useful.
     
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  19. arewenearlythereyet

    arewenearlythereyet Senior Member (Voting Rights)

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    The way I believe it is explained is that ATP is needed by the brain to function so when you are in deficit some non essential systems are put on "low energy consumption mode" cutting out all the non essential systems that eat a lot of energy (secretions, sensory processing etc). This makes some sense to a certain point ...but seems a little contrived. I think our main problem is that this then gets into an area we don't know very much about (restorative mechanisms while we rest/sleep etc). I'm always wary of theories that default to the "Unknown".

    I do know though that sensory processing uses up a lot of brain processing power, and when needed we turn off some non critical systems (digestion etc) to conserve energy so there might be something in it?
     
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  20. Rosie

    Rosie Established Member (Voting Rights)

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    Yes, I've experienced the different delay times as well. It all depends on what the exertion was (gardening, mental exertion, noise, etc. to name a few, is an exertion that brings on PEM quicker than other exertions for me).

    Then there is the 'accumulation' PEM that can happen over a period of time (weeks or months) this accumulation PEM is the worst in my experience. It produces a major deterioration and shift in ME levels and it's a long slow process to improve up the levels again.
     

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