Review: 'Through the Shadowlands’ describes Julie Rehmeyer's ME/CFS Odyssey
I should note at the outset that this review is based on an audio version of the galleys and the epilogue from the finished work. Julie Rehmeyer sent me the final version as a PDF, but for some reason my text to voice software (Kurzweil) had issues with it. I understand that it is...
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Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individua

Discussion in 'Latest ME/CFS Research' started by charles shepherd, Apr 3, 2015.

  1. charles shepherd

    charles shepherd Senior Member

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    Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome


    Julia Newton research involving muscle cell culture now published:
    Abstract

    Background

    Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS).
    Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS.
    To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.
    Methods

    Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.
    Results

    In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures.
    Control cultures subjected to 16h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells.
    In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16h EPS.
    However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect.
    IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.
    Conclusion

    EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells.
    We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6.
    The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.


    Full paper:

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982
     
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  2. Dolphin

    Dolphin Senior Member

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    Free full text: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982

    This study was funded by ME Research UK

     
    Last edited: Apr 3, 2015
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  3. Dolphin

    Dolphin Senior Member

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  4. alex3619

    alex3619 Senior Member

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    I find parts of this paper confusing. I have been trying to figure it out for a while. I need to come back to it after a rest.
     
  5. alex3619

    alex3619 Senior Member

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    I am trying to figure out what this means. I started reading this paper an hour or so back.

    The summaries are easy to read, but there is stuff in the paper I need to do some investigation on. Like the connection between AMPK and myocyte energy regulation, the connection between AMPK and myogenin, and why if we fail to increase glucose absorption when exercising does this lead to (presumed) elevated lactate? Or does it?
     
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  6. greeneagledown

    greeneagledown Senior Member

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    The most interesting thing about this to me is that it was done in vitro. I think that suggests that we're talking about a problem with the muscle cells themselves, rather than a secondary effect in muscle cells that is being caused by a difference in the levels of some sort of molecule in the blood. In other words, I may be mistaken, but I don't think what they've shown could result from anything that the bloodstream is (or isn't) carrying to muscles (cytokines, antibodies, etc.), or from a problem with blood flow -- otherwise they wouldn't be able to demonstrate the result in vitro. I think this is what they mean when they refer to a "primary abnormality in the muscle."
     
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  7. Dolphin

    Dolphin Senior Member

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    I think threads on research papers should be in the "latest ME/CFS research" section.
     
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  8. alex3619

    alex3619 Senior Member

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    That is the take some of us have had on this since we first heard about it last year. I was waiting for the publication. What it shows is there is something different in the muscle tissue itself. It also raises the question as to how a putative psychogenic disorder causes long term muscle changes that persist in vitro. The suggestion has been made this might be an epigenetic change. That is, the gene expression in these cells is altered. Its going to be very hard for psychobabble to keep claiming they have something useful to say as we get more and more research along these lines. It also puts pressure on vascular, brain and immunological hypotheses. As we get more data, more and more hypotheses will become untenable.
     
  9. Helen

    Helen Senior Member

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    "Conclusion

    ...The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets." My bolding.
     
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  10. lansbergen

    lansbergen Senior Member

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    But what causes that epigenetic mechanism?
     
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  11. alex3619

    alex3619 Senior Member

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    We are not even sure of the mechanism yet. It needs to be isolated. Once its isolated we can start asking what causes it ... but we might find an answer by chance before then, or using another line of investigation.

    The big thing here, which I paid attention to last year, is that drugs can first be tested on these tissue samples to see if they fix the problem, before subjecting any patients to trials.
     
  12. lansbergen

    lansbergen Senior Member

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    Yes
     
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  13. Persimmon

    Persimmon Senior Member

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    When Newton disclosed preliminary findings from this trial (that were reported in The Times newspaper several years back), she reported that ME/CFS muscle tissue exhibited abnormal lactic acid accumulation in response to simulated exercise. That outcome was consistent with the findings of her MRI study.

    As far as I can see, this paper doesn't disclose what happened to lactic acid levels.

    Can anyone explain? Have I missed something? Is this to be reported in a separate paper? Or might this omission suggest that they tested this, and didn't find abnormal lactic acid accumulation?
     
  14. snowathlete

    snowathlete Not an ol' sleazebag

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    And the value of that is hard to overstate; it is a massive benefit as you can quickly, safely and cheaply figure out what might work well and what probably won't. Likely it much increases your chances of getting funding for subsequent trials in actual patients as well.
     
  15. Dolphin

    Dolphin Senior Member

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    Sounds like this study:


     
  16. alex3619

    alex3619 Senior Member

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    I am also wondering about this. If (relatively) less glucose is absorbed, then why is lactate higher? It seems a contradiction. So maybe it wasn't higher in this test bed. Which raises questions about how much this might reflect in vivo muscle metabolism, that is how it works in the body.
     
    Last edited: Apr 3, 2015
  17. lnester7

    lnester7 Seven

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    Diabetes. 2002 Jul;51(7):2074-81.
    Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes.
    Musi N1, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ.
    Author information
    Abstract

    Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.
    http://www.ncbi.nlm.nih.gov/pubmed/12086935
     
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  18. lnester7

    lnester7 Seven

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    I was just wondering if this has been seen in other disease or if it is unique to CFS.
     
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  19. Sidereal

    Sidereal Senior Member

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    By "primary abnormality in the muscle" they mean the problem is peripheral (in the muscle) rather than central (in the brain). Since the early 1990s we've been fed psychobabbly hypotheses about central fatigue. The fact that muscle metabolism is abnormal in vitro would seem to cast serious doubt on such explanations.
     
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  20. PDXhausted

    PDXhausted Senior Member

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    This is kind of a stretch, but hypothetically speaking, if there were some kind of neurotropic (myotropic?) intracellular pathogen, could that explain the persistent abnormalities in vitro? Or would it be too unlikely to show up in all the samples?

    Or is it that if there were an infectious cause, the epigenetic changes in the muscle would persist ex vivo? Or no?
     
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