1. Guest, the 'News in Brief' for the week beginning 3rd May 2021 is here.
    Dismiss Notice
  2. Welcome! To read the Core Purpose and Values of our forum, click here.
    Dismiss Notice

Discriminatory cytokine profiles predict muscle function, fatigue and cognitive function in patients with ME/CFS. McArdle et al. 2020

Discussion in 'BioMedical ME/CFS Research' started by John Mac, Aug 22, 2020.

  1. John Mac

    John Mac Senior Member (Voting Rights)

    Messages:
    457
    Likes Received:
    5,405
    Full Title:
    Discriminatory cytokine profiles predict muscle function, fatigue and cognitive function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

    https://www.medrxiv.org/content/10.1101/2020.08.17.20164715v1?rss=1

    This was a study I took part in.

    Papers from the same study.
    https://bmjopen.bmj.com/content/bmjopen/7/11/e015296.full.pdf
    https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.31.1_supplement.lb789
     
    Last edited: Aug 22, 2020
    inox, Ravn, andypants and 11 others like this.
  2. Aslaug

    Aslaug Moderator Staff Member

    Messages:
    905
    Likes Received:
    5,002
    I did not know that MCV was different between pwME and healthy controls. Anyone know more about this?
     
    alktipping and Kitty like this.
  3. Andy

    Andy Committee Member (& Outreach when energy allows)

    Messages:
    12,892
    Likes Received:
    93,153
    Location:
    Hampshire, UK
  4. MeSci

    MeSci Senior Member (Voting Rights)

    Messages:
    3,041
    Likes Received:
    16,571
    Location:
    Cornwall, UK
    inox, Ravn, ukxmrv and 3 others like this.
  5. Trish

    Trish Moderator Staff Member

    Messages:
    32,167
    Likes Received:
    152,754
    Location:
    UK
    The paper says MVC, not MCV.

    I looked them both up.

    MVC apparently has lots of different medical meanings but this looks the most likely: maximum voluntary contraction

    [MCV is mean corpuscular volume]
     
  6. Aslaug

    Aslaug Moderator Staff Member

    Messages:
    905
    Likes Received:
    5,002
    It was mean corpusclar volume I was thinking of and I'm pretty sure I would have picked that up if it was "common" :p I misread as you assumed :)
     
  7. Dolphin

    Dolphin Senior Member (Voting Rights)

    Messages:
    2,951
    Likes Received:
    16,418
    This is one of the set of studies the Medical Research Council funded in 2012, basically the first time the MRC had funded biomedical research. The ME Association also added in a little money for a study that was part of the project.
     
    Ravn, ukxmrv, Andy and 3 others like this.
  8. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

    Messages:
    2,769
    Likes Received:
    19,176
    Location:
    Australia
    The problem with statistical models like this is that they don't tend to replicate.

    The sample size was decent, but 92 male patients and 63 female patients seems like an odd ratio.

    On the neuropsychological/cognitive testing, patients had the usual poor reaction times and poorer verbal memory, suggesting poor concentration.

    Maximal voluntary contraction was lower in patients than controls, there was no difference in the generation of maximal involuntary contraction by electrical stimulation between the two groups overall and at any frequency (relative to MVC). Given that this is relative to MVC, this is expected, it simply suggests that patients were producing sufficient maximal effort.

    Notably, during the "fatigue resistance test" the amplitude of electrical stimulation was not set at supramaximal levels. Instead set at "30% of the participants MVC force when stimulated at 100Hz".

    Looking at the graph, it is indeed curious that it was not statistically different. Given that the two seem to deviate further over time, it is possible that a difference would have emerged if the test went on longer than 2 minutes.

    Also note that fatigue during similar tests in muscular dystrophies and peripheral neuropathies have the same results, namely the fatigue is predominantly "central" in origin. The fact that the same pattern is observed in vastly different pathologies suggests that there is substantial coupling between peripheral afferents and "central fatigue", likely mediated through spinal feedback of type 3 and type 4 afferents, the purpose of which is to reduce the rate of unexpected peripheral fatigue (and thus makes force output more predictable to the brain).

    https://repository.ubn.ru.nl/bitstream/handle/2066/50860/50860.pdf (2006 thesis by Joke Kalkman. Studies compared fatigue in myotonic dystrophy, facioscapulohumeral dystrophy, and Hereditary Motor and Sensory Neuropathy type I - patients had less peripheral fatigue than health controls)
     
  9. cassava7

    cassava7 Senior Member (Voting Rights)

    Messages:
    309
    Likes Received:
    3,054
    Just a small typo, there were 29 male patients.
     
    Woolie, Snow Leopard, Ravn and 6 others like this.
  10. Hutan

    Hutan Moderator Staff Member

    Messages:
    13,423
    Likes Received:
    55,317
    Location:
    New Zealand
    (I worked on this this morning, before running out of energy. I agree with Snow Leopard about the fatiguability study - it looked as though there was or soon would have been a significant difference.)

    The authors have covered a lot in this paper. Good to see that they are referring to ME/CFS (mostly - still some use of CFS in places in the paper) and 100% of the cohort reported suffering from PEM.

    Here's some commentary about what they found out about just
    Muscle function and fatigue in patients with ME/CFS

    Voluntary muscle contraction
    They note that the people with ME/CFS had lower mean voluntary contraction force (MVC).
    Figure 1A
    Screen Shot 2020-08-23 at 7.45.02 AM.png
    There is a difference in age and gender of the ME/CFS and Healthy control samples - there was some adjustment for that. There's text that suggests that the difference in MVC has a p value of 0.0272 after adjusting for age and gender. So, it's not a particularly strong difference. The difference might just be a product of residual unadjusted effects of the ME/CFS sample having a higher percentage of females, an older mean age and more people with a sedentary lifestyle.

    My experience is that my muscle strength is variable - at times I think it's similar to what is typical for a woman my age, and then other times I just can't summon up adequate muscle strength. Walking up steps can be fine one hour and then later take a ridiculous amount of effort. So, I'm happy to assume that the difference in MVC they found is real.


    Actin-myosin filament interactions
    They report that there were no differences in the contractions in 'isolated skinned muscle fibres'. They stimulated the fibres with electricity and tested by increasing calcium concentrations. The authors felt this proved that the actin-myosin filament interactions were fine.

    Involuntary contraction of muscles in lower limb
    They found that involuntary contraction of lower limb muscles (by electrical stimulation) produced similar contraction forces in the ME/CFS and healthy control cohorts. Again, there was some unspecified adjustment for age and gender differences in the sample. I didn't see a P value for this. There does look to be a bit of a trend to lower forces in the CFS sample. I wonder what would be found if the ME/CFS people had only been tested when in PEM.

    Figure 1B
    Screen Shot 2020-08-23 at 8.05.33 AM.png

    Muscle fatiguability
    They tested fatiguability of involuntary contractions. See figure 1C - (duration on the x-axis), it looks as though the ME/CFS cohort's muscles became increasing less effective over time, relative to the controls. However, the text notes that there was no significant difference and doesn't give a P value. The conclusion is that there is no difference. It makes me wonder if the ME/CFS cohort was mixed, with some people not actually having ME/CFS - or perhaps some had PEM prior to testing and some did not. And also if the adjustment for age and gender was appropriate.

    Figure 1C
    Screen Shot 2020-08-23 at 9.00.10 AM.png

    Atrogen-1 levels
    They found lower levels of atrogen-1 in the muscle biopsies of the ME/CFS cohort, compared to the controls, reportedly suggesting an increase in protein degradation processes. This looks like a real difference. The question is, is this something specific to ME/CFS or is it just a product of reduced muscle mass as a result of a sedentary lifestyle. The finding looks worth investigating a bit more.

    Figure 3c
    Screen Shot 2020-08-23 at 10.50.01 AM.png
    They also found a larger percentage of small muscle fibres in the ME/CFS cohort relative to the controls.

    tl:dr
    So, the paper concludes that people with ME/CFS have lower voluntary muscle contractile force, but involuntary force (measured by electrical stimulation) is not different. I don't think this study conclusively proves that, especially under conditions of PEM and longer repeated use.
     
    Last edited: Aug 24, 2020
    inox, Ravn, Michelle and 8 others like this.
  11. garden

    garden Established Member

    Messages:
    6
    Likes Received:
    24
    "in situ"

    "permeabilization with saponin"

    news to me that pwme have surfactants surrounding their muscles! .... (sarcasm )
     
    Hutan, Ravn and Michelle like this.
  12. Hutan

    Hutan Moderator Staff Member

    Messages:
    13,423
    Likes Received:
    55,317
    Location:
    New Zealand
    Something to consider is that not all of the participants were included in each sub-study. So, for the muscle testing in vivo, there were only 15 people with ME/CFS. For the muscle biopsy, it varied according to the different tests done, but were only between 7 to 12 people with ME/CFS.
     
    Kitty, inox, Trish and 5 others like this.
  13. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

    Messages:
    897
    Likes Received:
    6,150
    Thought I would quote the abstract of Micheal VanElzakkers paper "Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods"
    Paper : https://www.frontiersin.org/articles/10.3389/fneur.2018.01033/full
    Thread : https://www.s4me.info/threads/front...-methods-michael-vanelzakker-et-al-2018.6758/

    I tried to scan the paper of this thread a few times but could find no detailed description of when they took the blood and how exactly it was processed. Did they use the same equipment and operators for patients and controls and were samples processed together. Montoya went to great lengths in his study to try and even control for centrifuge by alternating samples in slots of the machine.

    In Montoya's large Cytokine study paper the "Cytokine Assay" section describes the lengths he went to to ensure good quality. The "Statistical Analysis" section talks about techniques to remove plate effects.

    Paper : Cytokine signature associated with disease severity in chronic fatigue syndrome patients
    https://www.pnas.org/content/114/34/E7150

    "Cytokine Assay" section
    "Statistical Analysis" section
     
    Hutan, Kitty, inox and 4 others like this.
  14. Ravn

    Ravn Senior Member (Voting Rights)

    Messages:
    1,354
    Likes Received:
    11,556
    Can somebody explain figure 2B and the text relating to it?
    So the text says no significant difference in muscle fibre generated mitochondrial superoxide, neither with nor without addition of a nitric oxide synthetase inhibitor. Yet the graphs seem to show a difference. Figure 2B shows complete separation of ME from HC from the 40 minute mark, with the trend suggesting even further separation with more time. So why is this not significant?
    ME mtROS graphs.JPG
     
  15. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

    Messages:
    2,769
    Likes Received:
    19,176
    Location:
    Australia
    It is certainly confusing. I had to double check Table 1 to confirm that you were right!

    The error bars don't suggest statistical significance. The lack of significance is likely due to lack of sample-size and within-group variability.
     
    Last edited: Aug 24, 2020
  16. Amw66

    Amw66 Senior Member (Voting Rights)

    Messages:
    4,465
    Likes Received:
    21,222
    Do we know the ratio of male / females tested?
    Asking as some studies have suggested that females utilize protein differently - might this not affect muscles and perhaps indicate catabolization ?
     
    Michelle, MeSci, Kitty and 2 others like this.
  17. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

    Messages:
    2,769
    Likes Received:
    19,176
    Location:
    Australia
    It doesn't say what the ratio is, unfortunately.

    Given that this is a pre-print, some things can be updated if we are able to notify the authors!
     
    Michelle, Kitty, Hutan and 3 others like this.
  18. Andy

    Andy Committee Member (& Outreach when energy allows)

    Messages:
    12,892
    Likes Received:
    93,153
    Location:
    Hampshire, UK
    Comments can be left on the pre-print itself, and it also picks up tweets that mention the pre-print somehow.
     
    Michelle, Dolphin, Kitty and 3 others like this.

Share This Page