Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
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The Role of Cytokines in Muscle Fatigue in Patients with Chronic Fatigue Syndrome

Discussion in 'Latest ME/CFS Research' started by Nielk, Apr 2, 2015.

  1. Nielk

    Nielk

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    http://www.occupycfs.com/2015/03/31/assessing-outcomes/

     
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  2. charles shepherd

    charles shepherd Senior Member

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    This research is being funded by the Medical Research Council and The MEA Ramsay Research Fund.

    I'm just about to write a comment to accompany our website report!
     
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  3. charles shepherd

    charles shepherd Senior Member

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    More information on this research:



    MR/J002895/1

    PI: Professor Anne McArdle, University of Liverpool

    Title: Determination of mitochondrial function and cytokine production in skeletal muscle of patients with CFS.

    Start Date: 01/05/2012

    End Date: 30/04/2015

    Award Amount: £252,030.40 (co-funded with The ME Association Ramsay Research Fund)

    Lay Summary

    Chronic fatigue syndrome (CFS) is a severely debilitating illness of uncertain cause. CFS is characterised by prolonged, debilitating fatigue that can be triggered by minimal activity (NICE, 2010). The fatigue is accompanied symptoms which can include painful muscles and joints, disordered sleep, gastric disturbances and cognitive impairment and is sometimes associated with depression. CFS can affect people of any age but is most common between the ages of 25 and 45. Evidence suggests between 150,000 and 250,000 people are affected in the UK. The effect of CFS on quality of life is substantial, with some individuals becoming housebound, employment becoming difficult or impossible, disrupted education in younger sufferers and thus represents a substantial effect on the quality of life for people with the condition, their families and carers.

    The mechanisms by which an initial event leads to the chronic debilitating muscle fatigue and pain are unknown. The time required for diagnosis (typically 4 - 6 months) further complicates the identification of the factor(s) responsible for initiation of the illness. Irrespective of the factor(s) which initiates the illness, reversal of the severely debilitating fatigue which ensues remains the most promising form of treatment.

    A number of studies have suggested that there is a defect in the energy producing components of muscle cells, known as mitochondria but, although this is core to understanding muscle fatigue in patients with CFS, the presence of abnormal mitochondria in muscle of patients with CFS remains the subject of considerable debate as other studies have failed to demonstrate a defect. The reasons for such different findings are likely due to the previously limited methods of analysis for mitochondrial function with a lack of availability of appropriate and sensitive techniques to determine mitochondrial function directly in human muscle fibres. However, a new technique to study mitochondria in muscle fibres in situ from humans has now been developed and is established in our laboratory.

    We hypothesise that the application of these newly developed techniques will demonstrate that skeletal muscle mitochondria in patients with CFS are dysfunctional and that this results in muscle fatigue. The dysfunctional

    mitochondria then activate a process which leads to a chronic, low grade inflammation, commonly reported in patients with CFS, which in turn results in further mitochondrial abnormalities and the establishment of a vicious circle of events. Understanding the processes by which muscle fatigue occurs will lead to optimal interventions that break this vicious circle and improve muscle function and wellbeing of individuals.

    Technical Summary

    Chronic Fatigue Syndrome (CFS) is a severely debilitating illness of uncertain cause, characterised by prolonged, debilitating fatigue. Reversal of the severely debilitating fatigue which ensues remains the most promising treatment. The presence of abnormal mitochondria in muscle of patients with CFS remains the subject of considerable debate. The reasons for such different findings are likely due to the previous lack of availability of appropriate and sensitive techniques to determine mitochondrial function directly in muscle fibres. However, to study mitochondrial function in muscle fibres in situ from humans, a method of isolating bundles of muscle fibres and permeablisation with saponin has been developed. This technique is established in our laboratories and will lead to a definitive answer regarding a mitochondrial defect in muscles of patients with CFS. Chronic ROS generation by muscle mitochondria is proposed to result in chronic activation of NFkB and subsequent lowgrade inflammation. We further hypothesise that activation of NFkB results in muscle becoming a major source of systemic pro-inflammatory cytokines, resulting in further mitochondrial abnormalities and the establishment of a vicious circle of events. Interventions that modify mitochondrial ROS generation or NFkB activation in muscles will reduce systemic inflammation, break this vicious circle and improve muscle function.This application is a new collaboration between basic scientists at the University of Liverpool, experts on diet and cognitive function at the University of Leeds and a consultant in Infectious disease and Tropical medicine with a special interest in CFS/ME. We will apply a novel technique to examine mitochondrial function in muscle cells in situ and determine the role of muscle in the production of inflammatory mediators.
     
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  4. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    Would it not have been better to also have deconditioned healthy controls? Doesn't this study leave the door open for the usual deconditioning arguement?
     
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  5. charles shepherd

    charles shepherd Senior Member

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    Yes, that is a very fair point and I am keen to see 'deconditioned (otherwise) healthy controls' in ME/CFS research studies

    But we do not have this type of control group in this on-going mitochondrial function study

    In fact, I can't think of many ME/CFS research studies that have used deconditioned healthy controls

    One problem is where do you get these 'deconditioned healthy controls' ?

    People in prison who do very little exercise is one possibility - but the ethics and practicalities do not appear to allow it

    PS Like your ref to LC. Been to see him twice in the past few years. LC still turns out an amazing live performance! No deconditioning there…...
     
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  6. duncan

    duncan Senior Member

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    This is a very interesting piece, with some good information.

    I just have a couple of questions.

    Are you at all concerned that this may come across a bit top heavy on fatigue emphasis? Not sure where the support could be found for "Reversal of the severely debilitating fatigue which ensues remains the most promising treatment." Also, might this latter sentence suggest multiple promising treatments are already at our disposal?

    Finally, do you think it wise to throw in, early in the first paragraph " and is sometimes associated with depression"? Isn't that inviting the reader to misconstrue?
     
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  7. Snow Leopard

    Snow Leopard Hibernating

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    I think a better question is, why weren't (explicit) sedentary controls being used?
     
  8. user9876

    user9876 Senior Member

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    Or even the same techniques applied to a range of healthy people with different activity patterns to look if there is correlation between activity patterns and the various measures. I would prefer to understand healthy controls as a continuum rather than after being placed into classes.
     
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  9. charles shepherd

    charles shepherd Senior Member

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  10. charles shepherd

    charles shepherd Senior Member

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    These are quotes/opinions from the research group

    As a funder, I think it's reasonable to say that relief from severe debilitating (muscle) fatigue is both a promising and important part of any research study that is looking at skeletal muscle pathology - and this study does also have a 'looking at possible forms of treatment' component added to it

    'Sometimes associated with depression' is a term that I also use at times
     
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  11. charles shepherd

    charles shepherd Senior Member

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    The healthy controls will have a range of activity levels and this can be looked at if necessary.

    But we don't have an inactive/sedentary/deconditioned health controls for reasons already stated.

    As I've already said, I accept that this is a perfectly valid point
     
  12. snowathlete

    snowathlete

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    I'm using a potent herbal NFkB inhibitor which seems to be helping a little. Hard to judge though.
     
  13. Nielk

    Nielk

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    Would this explain the "myalgia" such as in "myalgic encephalomyelitis"?
     
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  14. user9876

    user9876 Senior Member

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    I'm having trouble associating the abstract describing the TNF-alpha and muscle testing with the description of the work talking of mitochondria testing. I'm assuming that there will be more results talking about mitochondria in the future?
     
  15. charles shepherd

    charles shepherd Senior Member

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  16. charles shepherd

    charles shepherd Senior Member

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    Possibly

    It's certainly an interesting hypothesis:

    fluctuating cytokine activation in skeletal muscle >> fluctuating and activity induced muscle pain……..
     
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  17. charles shepherd

    charles shepherd Senior Member

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    There are several components to this study - including work that is more focussed on mitochondrial function
     
  18. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I don't know the detail but the result on electrical stimulation (no difference in fatiguing of muscle, whatever this is measured as) may deal with this. If ME muscle in fact is not deconditioned but works just as well as healthy muscle when stimulated involuntarily that may be more interesting than trying to find a valid 'deconditioned' comparator.
     
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  19. charles shepherd

    charles shepherd Senior Member

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    Anne McArdle gave a short presentation on this research at the CMRC Conference in Bristol last year.

    From the conference report:

    Mitochondrial function and cytokine production in skeletal muscle of patients

    with CFS/ME

    Prof Anne McArdle, University of Liverpool

    Prof McArdle began by saying that this project is almost completed in terms of

    sample gathering. “But what I can’t do today is show you any data because the

    project is blinded,” she continued. “We are finalising the collection of our blood

    samples in particular and we don’t want to compromise the analysis.

    “Hopefully what I can do instead is convince you that we are on the right track. I am

    going to show you some comparative data, particularly from our aging studies, to

    show you why we are taking this approach.”

    The study is exploring muscle abnormalities in CFS/ME through the use of new

    techniques which can more accurately assess the way in which the mitochondria –

    organelles responsible for energy production – are behaving in muscle in CFS/ME.

    This new research in Liverpool has made use of various experimental systems they

    have developed using both in vitro (studies on tissues removed from a living

    organism under artificial conditions in a laboratory) and in vivo (studies on tissues

    not removed from a living organism) experiments to look at the way in which

    mitochondrial function can be linked to cytokine changes.

    Prof Jonathan Edwards comments: “Prof McArdle gave us an account of how

    mitochondrial function, generation of reactive oxygen species and Adenosine

    triphosphate [how muscle cells biochemically store and use energy] handling in

    muscle are all tied in to signalling through cytokines like TNF. Muscle mitochondria

    are different from those in other cells in their position and density.

    “She described a range of experimental systems used in Liverpool both in vivo and

    in vitro to study the ways in which mitochondrial function might be linked in to

    cytokine changes. She indicated the importance of feedback loops that could

    potentially set up long-term abnormalities of regulation of muscle metabolism.”
     
  20. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    The URL at the top of the thread takes me to something else - which is very interesting but not this. Never mind. I really like this abstract. It feels like the real stuff to me. The bits of data you need are there and the interpretation is very simple and professional. And having heard Anne McArdle talk I have no doubt that this is quality research. I don't think we got anything quite as tangible as this in Bristol but this is looking nice.
     
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