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Does muscle bioenergetic abnormality cause peripheral fatigue in ME/CFS?.

Discussion in 'Latest ME/CFS Research' started by aalia_12, Feb 2, 2011.

  1. aalia_12

    aalia_12

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    Does muscle bioenergetic abnormality cause peripheral fatigue in ME/CFS?
    Investigators
    Prof. David Jones and colleagues

    Institutions
    Institute of Cellular Medicine, University of Newcastle, Newcastle upon Tyne, UK

    Background and aims
    In the historical literature, the hallmark of myalgic encephalomyelitis (ME) was marked muscle fatigability often in response to minor degrees of exercise. Muscle cramps, fasciculations (twitching) and extreme muscle tenderness were also common findings. As Dr Ramsay said in the Postgraduate Medical Journal in 1978, This was sometimes obvious as the patients winced even on light palpitation of the affected muscle; but much more frequently it took the form of minute foci of muscle tenderness which had to be carefully sought and for no ostensible reason were generally found in the trapezii and gastrocnemii.

    Today, patients diagnosed with ME/CFS frequently highlight the importance of peripheral fatigue such as impairment of muscle power in their experience of illness. Research in other chronic diseases, including published work by Prof. Jones at the Institute of Cellular Medicine on the autoimmune liver disease primary biliary cirrhosis, has highlighted important downstream biological mechanisms that appear to underpin fatigue. A number of these processes are, intriguingly, common to many chronic diseases, including ME/CFS; previous work has highlighted the frequency with which dysfunction of the autonomic nervous system is seen in both ME/CFS and primary biliary cirrhosis patients, as well as patients with many other conditions. The potential for shared mechanisms behind the expression of fatigue (if not its pathogenesis) is suggested by other recent work in the Institute of Cellular Medicine highlighting the close similarities in the phenotype of fatigue seen in a number of chronic diseases and ME/CFS.

    In novel studies at the University of Newcastle using magnetic resonance scanning of peripheral muscle in ME/CFS patients (a scanning technique which looks at the way in which muscle is working), significant abnormalities in the handling of acid within muscle during exercise have been observed. It might be that acid build-up during exercise in ME/CFS patients results from reduced function of an important energy-generating enzyme within the mitochondria (the batteries of the cell) causing peripheral fatigue which feeds-back to the brain.

    Given these findings, the aim of this project is to study, in the in vitro setting, the function of an energy-generating enzyme which the researchers hypothesise might be under-functioning in ME/CFS. A range of in vitro studies will be undertaken, all based on primary assay and culture of muscle cells (myocytes) derived from ME/CFS patients (fulfilling the Canadian criteria for ME/CFS) and matched normal and chronic disease controls (following establishment of the techniques using existing myocyte cell lines).

    There are two broad aspects to the proposed investigative strategy. In the first (already funded by the Northern Clinical Network in Newcastle), an examination will be made of the function of ME/CFS patients muscle cells which have been grown in culture; the muscle biopsies taken during this phase represent a unique opportunity to study the pathways of metabolism within muscle, exploring the expression of the key energy generating enzymes and the cell proteins which help to control acid build up within the cell. The second aspect (funded by ME Research UK) involves array studies to look at metabolic gene expression in muscle. It is hoped that the results will show whether gene expression is altered in cultured muscle cells from patients with ME/CFS, and whether the change in gene expression with exercise in vitro is impaired in these muscle cultures.

    This interesting range of studies builds on existing academic strengths in muscle energetics and culture, together with nanotechnology development, all of which are applied to the illness ME/CFS for the first time.
    http://www.meresearch.org.uk/researc...nergetics.html

    -->> trapezii
    Main Entry: trapezius
    Pronunciation: \-z-əs\
    Function: noun
    Inflected Form(s): plural -zii \-z-ˌ\ also trapeziuses
    Etymology: New Latin, from trapezium; from the pair on the back forming together the figure of a trapezium
    Date: circa 1704
    : a large flat triangular superficial muscle of each side of the upper back

    .
  2. Dolphin

    Dolphin Senior Member

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  3. Glynis Steele

    Glynis Steele Senior Member

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    Newcastle upon Tyne UK
    Hi,

    I find these studies very interesting, thanks Aalia and Dolphin. Notice in the study aalia provided it talks about problems with acid build up.

    And in the second link that Dolphin provided, which can be found below, it talks about pH handling and says the objective was to examine muscle acid handling following exercise. In the conclusion it says CFS patients have abnormalities in recovery of intramuscular pH:

    .

    http://www.forums.aboutmecfs.org/sho...regulation-by-

    I just wanted to ask the clever folk here whether the acid that is mentioned could be d-lactic acid? D-lactic acid is hypothesised in the KDM/Sheedy paper as being involved in CFS. A study taking this research further begins this month in Australia, here is a link explaining this.

    http://sacfs.asn.au/download/Lactic acid study 2008 - Ethics Application.pdf

    D-lactic acidosis causes a change in the anion gap, and therefore changes the pH in the bowel and blood. However, it can occur without a change in the gap, making testing impossible without a specific test measuring the d-lactate. This is not normally carried out by path labs, path labs do not normally have this test available, and it has to be shipped in.

    Clinical presentation, the plasma anion gap

    There are two major ways acidosis is defined from routine
    laboratory data. First, organic acids may be added to the body so
    quickly that both the H and the anion are retained; this results
    in metabolic acidosis and an elevated value for the plasma anion
    gap [6466] (upper right portion of Fig. 6). Second, metabolic
    acidosis may be present without a rise in the plasma anion gap. In
    this latter setting, either the D-lactate anion was retained in the
    lumen of the GI tract (with the H being absorbed or titrated by
    bicarbonate in the lumen of the GI tract), or it was excreted in the
    urine, but in either case, the cation lost with it was Na and/or K
    ion
    [671 (not a H or NH4 ion, lower right portion of Fig. 6).
    This latter type of metabolic acidosis is akin to the over-production
    of hippuric acid in glue sniffers [68]. Since D-lactate anions
    are reabsorbed by the kidney much less readily than is L-lactate
    [54, 69, 70], as time progresses, the anion gap may decline without
    resulting in a rise in the plasma bicarbonate concentration-that is,
    D-Iactate is excreted as its Na or K salt (Fig. 6). Hence there
    are a number of mechanisms that may contribute to the presentation
    whereby the rise in the plasma anion gap might not match
    the fall in the plasma bicarbonate concentration. Not only might
    this lead to a diagnostic problem, it has implications for therapy
    because, once the organic anions are excreted as their Na or
    salts, these anions are no longer available for metabolism to
    regenerate bicarbonate, and the patient might have developed a
    deficit of Na and/or K4.

    And from another article about the anion gap:

    "There are, however, conditions in which the unmeasured anion is not reabsorbed. As a result, the anion will be rapidly eliminated from the plasma, potentially normalizing the anion gap. One example is D-lactic acidosis. This rare disorder is seen with jejunoileal bypass or a short-bowel syndrome; it is due to the combination of bacterial overgrowth and increased glucose and starch delivery into the colon (due to lack of normal absorption in the small intestine). As a result, dietary carbohydrate is converted to D-lactate, rather than the physiologically occurring L-lactate. (See "D-lactic acidosis"). The proximal sodium-L-lactate cotransporter is stereospecific and does not bind D-lactate. Thus, this anion is quickly excreted in the urine"

    Here is a link to d-lactate acid symptoms, this questionnaire was used as part of the Australian study into d-lactic acid in CFS patients. Many of the d-lactic symptoms apply to CFS patients

    http://www.sacfs.asn.au/download/Lactic acid study 2008 - Bioscreen Questionnaire.pdf

    Sorry about the amount of links, there's a lot to take in here. However I wanted to point out that d-lactic acidosis is a treatable condition, usually overseen by a GI who would monitor the d-lactic levels, and treat. D-lactic is not meant to be seen in a healthy person, so the Australian study might give us all a valuable insight as to what is going on in CFS, and also treatment options.

    Glynis

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