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Cellular bioenergetics is impaired in patients with chronic fatigue syndrome

Discussion in 'Latest ME/CFS Research' started by Cheesus, Oct 24, 2017.

  1. Cheesus

    Cheesus Senior Member

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    Tomas C, Brown A, Strassheim V, Elson J, Newton J, Manning P (2017) Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS ONE12(10): e0186802. https://doi.org/10.1371/journal.pone.0186802

    Abstract
    Chronic fatigue syndrome (CFS) is a highly debilitating disease of unknown aetiology. Abnormalities in bioenergetic function have been cited as one possible cause for CFS.

    Preliminary studies were performed to investigate cellular bioenergetic abnormalities in CFS patients. A series of assays were conducted using peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls.

    These experiments investigated cellular patterns in oxidative phosphorylation (OXPHOS) and glycolysis. Results showed consistently lower measures of OXPHOS parameters in PBMCs taken from CFS patients compared with healthy controls.

    Seven key parameters of OXPHOS were calculated: basal respiration, ATP production, proton leak, maximal respiration, reserve capacity, non-mitochondrial respiration, and coupling efficiency.

    While many of the parameters differed between the CFS and control cohorts, maximal respiration was determined to be the key parameter in mitochondrial function to differ between CFS and control PBMCs due to the consistency of its impairment in CFS patients found throughout the study (p≤0.003).

    The lower maximal respiration in CFS PBMCs suggests that when the cells experience physiological stress they are less able to elevate their respiration rate to compensate for the increase in stress and are unable to fulfil cellular energy demands.

    The metabolic differences discovered highlight the inability of CFS patient PBMCs to fulfil cellular energetic demands both under basal conditions and when mitochondria are stressed during periods of high metabolic demand.


    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186802
     
  2. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    The biochemistry is above my head, but theyve used Fukuda-criteria with strong p-results. Would love for someone to break this down, seems pretty significant and legit on first glance. Obviously need replication as they say so themselves
     
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  3. A.B.

    A.B. Senior Member

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    p<0.001 on many results after Bonferroni correction for multiple comparisons. I don't think these results are due to false positives :D.

    Notable that they used a Seahorse. It seems that what was needed to find abnormalities was more the right tech and knowledge, rather than the right case definition.
     
    Last edited: Oct 24, 2017
  4. Never Give Up

    Never Give Up Collecting improvements, until there's a cure.

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    That Seahorse is really coming through for ME/CFS!
     
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  5. Londinium

    Londinium Senior Member

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    Just going through it now but my first (parochial) thought is, wow, this is BRITISH research. Actual British research that doesn’t involve false illness beliefs, beat-em-harder exercise techniques, or expensive magic circles devised by tarot practitioners.

    The tide is turning.
     
  6. simeyss

    simeyss

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    That must feel SOOOOOO good to see! Finally, eh? :)
     
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  7. Murph

    Murph :)

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    So: they found big differences in several measures of cellular energy production.

    "Results showed that CFS patients can only increase their respiratory capacity 47% (±37%) from baseline when maximally stimulated by FCCP, which is significantly (p<0.001) lower than the 98% (±32%) increase in respiratory capacity achieved by control PBMCs"

    The differences got even bigger when they stressed the cells by depriving them of glucose.

    "A higher maximal respiration in low glucose conditions was only observed in the control cohort but not the CFS cohort, while basal respiration did not increase significantly in either cohort in the low glucose conditions. Additionally, the control cohort increased ATP production, non-mitochondrial respiration and coupling efficiency, and decreased proton leak, in low glucose conditions. The CFS cohort showed no differences between low and high glucose conditions in any of the parameters. This may be due to the control cells being more adaptable to their environment and possessing an ability to increase their ATP production via mitochondrial respiration when required–something the CFS cells may not be able to do."

    This is a big clear finding of something being wrong. decent sample size, some very low p values, and correction for multiple comparisons. Should hopefully focus brains on metabolism.

    Couple of notes though- they used the Fukuda definition, which many people think is too broad. They had no data on the patients severity, symptoms etc so correlating severity with the data wasn't possible.
    Also, they measured cells outside of serum. Previous research suggested that 'something in the serum' was affecting cells, rather than the cells themself being faulty. We need to figure out which is true.
    Also, they found glycolysis working normally, which contradicts some previous research.
     
    Last edited: Oct 24, 2017
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  8. AdamS

    AdamS Senior Member

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    So this explains why even after waking up I still rarely have a perceived energy level of above 6/10. I've always wondered why I never feel entirely normal even when laying down.

    Interesting. Does this differ slightly from Ron Davis's metabolomics findings? Or does it suggest that in the very severe, both anaerobic glycolysis and the more efficient OXPHOS pathway are broken?

    Seems like a fair acknowledgement...i'm liking this study the more I read it.

    I'd hazard a guess that these bioenergetic abnormalities contribute greatly to the fatigue. When demand is greater than supply something usually has to give and in our case it seems that this deficit causes a cascade of insults over time which inevitably lead to pain and fatigue. These insults could be inflammatory or in the form of alterations of peripheral sensory signalling in my view as discussed here by Alan Light. I'd be interested to hear other people's thoughts. I found this study to be very interesting.
     
    Last edited: Oct 24, 2017
  9. Murph

    Murph :)

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    Agree! Seems too cautious to say the measured effects could be caused by feelings of fatigue than the reverse.

    BUT: what is causing the abnormalities? Is it the body's own systems dialing down metabolism as some sort of protective effect? Is there some sort of calcium channel effect or cytokine still present in these PBMCs - even after washing and freezing and thawing - that could be signalling them to play it cool on the energy burning?

    Activity could be really important. I wonder if you'd get a different result with PBMCs taken during PEM vs not PEM.
     
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  10. AdamS

    AdamS Senior Member

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    Personally I don't think it's a protective mechanism. It seems that ME/CFS cells are performing at the maximum rate of efficiency possible but this rate is limited by a bottleneck (perhaps insufficient supply of acetyl-CoA or impairment of PDH function). My view is that chronic immune activation is at least partly behind this, I always think back to when I came down with a suspected case of Swine flu after going on holiday in 2009...my symptoms were extremely similar to ME, I couldn't walk further than about 200 yards and was bedbound for about 7-10 days before I finally recovered. So it seems that the immune system is capable of inducing many of the symptoms we experience in ME, what I can't explain is the extreme state some of us find ourselves in when we crash, the severe light/noise sensitivities, pain, restless legs etc. Perhaps there is some collateral damage caused by the initial crash which impacts signalling too.

    This is the bit I was talking about re ME cells performing at the maximum rate of efficiency.
     
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  11. alex3619

    alex3619 Senior Member

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    I will need to read this paper a few more times before I say anything, but this test might be used as a possible confirmatory test for CFS, and more likely for ME. Its a research test though, so I am not sure if its going to be useful clinically. However it is in agreement with the CPET data, and may in fact be the long awaited alternative to CPET.

    What I have been saying lately about CPET is that it cannot be used to diagnose ME, but it can be used to exclude an ME diagnosis except possibly in mild cases. I think this is the same. Normal mitochondrial flux under the conditions tested will probably mean the person does not have ME.
     
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  12. halcyon

    halcyon Senior Member

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    It's impossible to compare the various studies out because I don't think any of them detail the phenotype of the WBCs they're studying and this does matter when it comes to metabolic function. I hope that from here we can move away from using WBCs for this type of research because it introduces confusion and seemingly conflicting results. It's time to start looking at organ and muscle cells.
     
  13. Murph

    Murph :)

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    presumably much harder to get biopsies than blood draws, though, right?

    More intrusive, more painful, more training needed for nurses, harder to get large volumes that can be tested for many different features.

    I'm not saying you're wrong but it would make research pricier I guess.
     
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  14. halcyon

    halcyon Senior Member

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    Of course, but it's what's needed. They're assuming that what they're finding reflects the rest of the body but immune cell metabolism can be decoupled and look different than the rest of the body based on what the cell is exposed to or how it differentiates.
     
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  15. anni66

    anni66 mum to ME daughter

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    Spookily this ties in very neatly with the ATP profiles test we had done for daughter.
     
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  16. viggster

    viggster Senior Member

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    The Seahorse machine is getting to be popular for ME/CFS. The very small sample of Seahorse data I saw at NIH very broadly agrees with this study - CFS patients did not ramp up energy production in response to demand as well as controls, by a big margin. The NIH study is using white blood cells too, but the scientist running the machine really wants to get her hands on muscle cells.
     
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  17. nandixon

    nandixon Senior Member

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    If Mark Davis’ work is correct regarding CD8+ T cell expansion in ME/CFS, then the OXPHOS impairment they're seeing in this study may simply be the relevant T cells having undergone activation and consequently a switch to aerobic glycolysis away from OXPHOS for expansion/proliferation purposes - i.e., the usual process that T cells normally use when activated.

    In other words, this study may be confirming that a population of T cells is inappropriately activated - rather than there being some bodywide OXPHOS dysfunction that is also occurring in other cells like muscle, liver, etc (although deranged cytokine signaling from the activated T cells can potentially cause mitochondrial dysfunction in those other cells).

    Whether this is the case can perhaps be determined using the method the authors suggest themselves at the end of the paper:


    I also mentioned something related to this topic on the Fluge & Mella thread starting here.
     
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  18. Londinium

    Londinium Senior Member

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    My guess is that I can't see that it would be a good diagnostic test for now. If we take the measurements for which there is the biggest difference between CFS and Controls, say Fig 3.D or Fig 3.E (Maximal Respiration and Reserve Capacity, respectively), whilst there's a highly statistically significant difference between the groups, there is still a reasonable amount of overlap between the two. I think one would struggle to get a decent AUROC number when trying to diagnostically distinguish between the two groups - though it would be interesting if the authors calculated that in a follow-up paper.

    Edit: though I should note the overlap could be due to the diagnostic criteria used (Fukuda) picking up people with a different aetiology for their fatigue. All part of the fun of trying to research heterogeneous conditions that may be more than one underlying illness.
     
  19. Marco

    Marco Grrrrrrr!

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    Just a quick eyeballing of the figures suggests some 'outliers' in the CFS group.
     
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  20. A.B.

    A.B. Senior Member

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    Patients having a good day, or a case of misdiagnosis?
     
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