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Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS

Discussion in 'Latest ME/CFS Research' started by deleder2k, Dec 22, 2016.

  1. deleder2k

    deleder2k Senior Member

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    Fluge and Mella with a new study.

    From Kavlifondet.no:

    "A new study, partly funded by the Kavli Trust, suggests that the PDH enzyme is inhibited in ME/CFS patients, which may explain both energy shortage and increased lactate production in these patients. These findings have now been published in the Journal of Clinical Investigation Insight.

    By Øystein Fluge, Karl Johan Tronstad and Olav Mella

    [​IMG]Photo: Øystein Fluge, senior consultant and cancer scientist and Karl Johan Tronstad, professor.

    The Kavli Trust has supported ME research at the oncology department at Haukeland University Hospital since 2011. The cooperation with the Kavli Trust has enabled the group to engage in new projects and make scientific advances in the field of biomedical research on ME/CFS.



    [​IMG]Photo: Olav Mella, department head and professor and Kari Sørland, national project coordinator and nurse.



    Previously, the research group has published clinical studies investigating the use of the immune drug Rituximab in patients with ME/CFS (, [ii],[iii]). Rituximab is an artificially manufactured antibody which reduces the number of B-lymphocytes, a type of white blood cells which can develop into immune cells with a number of functions, among them antibody-producing cells. These studies have shown symptom improvement in approximately 60 % of patients treated with the drug. We hypothesize that ME in a subgroup of patients could be a type of immunological disease, in which B-cells and possibly adverse effects of antibodies play a part.

    Confirm or refute
    Five Norwegian hospitals are now collaborating on a clinical trial aiming to confirm or refute whether Rituximab can be useful in the treatment of ME patients. At Haukeland, the research group is also conducting a trial of moderate doses of the chemotherapy drug Cyclophosphamide, which has immunosuppressive effects and targets more parts of the immune system than the more specific Rituximab. Through these clinical studies, we are aiming to uncover possible treatment methods, while simultaneously working to shed light on the underlying symptom mechanisms in ME.

    Biochemical changes
    More than 200 patients have been included in our studies after thorough medical assessment according to internationally accepted («Canadian») criteria. These patients are subject to systematical and standardized follow-up in the studies, and regularly donate blood samples to a research biobank. Based on the material collected in the biobank, the research group has conducted a comprehensive and detailed mapping of the metabolism in 200 patients and 100 healthy controls. The project was supervised by the authors (Karl Johan Tronstad, Øystein Fluge and Olav Mella), and conducted in collaboration with Bevital AS and Per M. Ueland.

    As a result of these metabolic analyses, we detected specific biochemical changes in the blood of ME/CFS patients. These findings have now been published in the Journal of Clinical Investigation Insight.

    The analyses of blood samples from the ME/CFS patients showed that the levels of certain amino acids were reduced compared to healthy control subjects. The pattern of amino acid changes gave us important information about the symptom mechanisms, and in particular about the patients’ energy metabolism.

    [​IMG]May explain energy deficiency
    Under normal circumstances, human cells utilize carbohydrates, fats (lipids) and proteins (amino acids) as sources of energy, through catabolic processes in the mitochondria, the “powerhouses” of the cell. However, when we engage in intense physical exercise, there is a shortage of oxygen delivered to the muscle mitochondria (anaerobic exercise), at which point glucose is converted to lactic acid. Since lactate accumulates and there is lower energy yield, the body will say “stop” after a short time. The enzyme pyruvate dehydrogenase (PDH) plays an important role in the regulation of these processes, as it contributes to coordinating the utilization of carbohydrates, amino acids and lipids (fats) as energy sources. The new study suggests that the PDH enzyme is inhibited in ME/CFS patients, which may explain both energy shortage and increased lactate production in these patients.

    PDH enzyme dysfunction
    In previous international studies, reduced levels of certain specific amino acids in the blood of ME patients have been reported. In our new study, all 20 standard amino acids were analysed in the blood of 200 patients included in clinical trials as well as 100 healthy control subjects.

    A specific reduction in amino acids which are catabolized independently of the PDH enzyme was observed. This finding suggests that the PDH enzyme is not functioning as it should in ME patients, and as a consequence the cells increase the consumption of certain amino acids as fuel instead of glucose.

    The reduction in specific amino acids which convert to energy was primarily found in women with ME. In male ME patients, the differences in amino acid levels were less significant compared to healthy men. However, we found increased levels of one particular amino acid which reflects the breakdown of proteins in muscle tissue in male ME patients. Since men generally have larger muscle mass than women, proteins from muscle tissue can function as an extra energy reserve increasing the availability of amino acids as an energy source.

    Insufficient energy
    The PDH enzyme is a key component in one of the most important pathways for conversion of carbohydrates to energy – a process which takes place in the mitochondria. If the activity of the PDH enzyme is impaired, the cells may respond by increasing the consumption of alternative fuels, which may explain the changes seen in the amino acid profile in blood from ME patients. Despite the body’s attempts at compensation, this situation would compromise the cells’ ability to adapt the metabolic processes to suit the ever changing demands for energy production. For example, physical activity could result in a sudden shortage of energy in the muscles, coupled with a build-up of lactate. These are normal effects seen in healthy people during rigorous exercise, but in severely ill ME patients these symptoms can be observed after minimal strain, such as getting out of bed and walking a few steps. Feedback from study patients indicates that they can relate these findings to their symptoms, including a fundamental lack of energy, malaise and lactate pains after physical activity.

    When we proceeded to measuring the gene expression (mRNA) in white blood cells for a number of factors regulating the PDH enzyme, we found that several important factors which inhibit PDH function was increased in ME patients. Interestingly, these changes in gene expression were present in both female and male ME patients. These findings indicate that the PDH inhibition itself is the same for both men and women, but the effects on the metabolism may be partly gender specific.

    Further studies
    In all likelihood, ME also encompasses regulatory problems in other parts of the metabolism, e.g. in the processing of lipids (fats). This is now the subject of further studies. Based on the results from the metabolism study, we hypothesize that ME patients suffer from a PDH enzyme inhibition which involves both a reduced ability to produce energy from carbohydrates and an abnormal production of lactate in the muscle even after minimal strain. An important focus for the current research work is to gain understanding of how a presumably faulty immune response after an infection could warrant such an inhibition of the cellular metabolism.

    We theorize that the immune drugs on trial (Rituximab and Cyclophosphamide) affect the faulty signal from the immune system in such a way that the inhibition of the PDH enzyme is reduced. Thus the normal breakdown of glucose can be restored and the production of the body’s «energy currency», ATP, may adapt better to the patient’s activity level.

    We believe that the findings in the study are important for the understanding of ME/CFS as a disease, and consistent with two recently published reports on metabolic changes in ME/CFS. The anticipated consequences of the observed metabolic changes are compatible with the clinical picture demonstrated by ME patients.

    http://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-9-28

    [ii] http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026358

    [iii] http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129898"


    Source: http://kavlifondet.no/2016/12/new-study-on-pathological-mechanisms-in-me-from-bergen-research-group/


    Abstract:

    Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.


    http://insight.jci.org/articles/view/89376
     
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  2. deleder2k

    deleder2k Senior Member

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    Today's longshot: Could this be something worth trying out for Christmas?
     
  3. greeneagledown

    greeneagledown Senior Member

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  4. Cheesus

    Cheesus Senior Member

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    Is this a small part of a bigger metabolic picture or could this be right at the heart of the disease? I have no way of understanding the significance of these results in the context of existing research. Clarification from our resident experts would be much appreciated :)
     
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  5. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I need to sit and look at the data carefully several times. What I can say is that the paper is well written and makes a lot of sense in the way it is designed. Also the raw data plots are really helpful, with very nicely presented controls and stratification. I have no doubt that the differences described are both biologically and statistically significant.

    I guess the biggest 'if' question is if these findings relate to secondary changes or whether they tell us something about what causes the problem. I would not want to hazard a guess as yet but either way they loo as if they provide a definable biochemical shift to 'bootstrap' from towards a specific answer.

    Whether this is the big Christmas present we have all been waiting for or not may not be clear until the Easter Bunny has popped out of his hole but it will become clear soon enough.
     
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  6. A.B.

    A.B. Senior Member

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    This study also found that muscle cells cultured in serum from patients showed some energy metabolism abnormalities in comparison to those cultured in serum from healthy controls. They say
     
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  7. Ben Howell

    Ben Howell OMF Correspondent

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    Another Landmark study. Was suprised at the number of those involved-in a good way!

    All seems very much in agreement with Naviaux, Armstrong etc.

    Really good to see.


    B
     
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  8. roller

    roller wiggle jiggle

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    this is no landmark study.
    this was to be expected.
    it can straight go to the rubbish bin.

    could they at least reveal what pathogens and parasites the participants have been tested for (found with titres/not found)?

    if we had at least this info from such rubbish-studies, we could be there already...

    this is needed. and really, its just something that belongs to a scientific approach.
    for data analysis anyway. big data studies.
     
  9. Grigor

    Grigor Senior Member

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    I always make sure I read your expert opinion carefully. I think this one was well worth it. The best. Dank u wel
     
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  10. eljefe19

    eljefe19 Senior Member

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    Anyone have any ideas how to upregulate PDH?
     
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  11. A.B.

    A.B. Senior Member

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    It's worth noting that they have also found out how PDH is impaired. It's not an antibody apparently but some proteins whose purpose is to shut down PDH. This seems to fit into the coordinated state of hypometabolism concept.

    If the Rituximab results are correct, then at some point the chain of causation of this coordinated state of hypometabolism must pass through B cells.

    The question of whether this state is adaptive or maladaptive remains. Maybe shutting down PDH prevents a worse problem from appearing. Energy generation past PDH produces a lot of oxidative stress, maybe shutting down PDH serves the purpose of minimizing oxidative stress.
     
    Last edited: Dec 22, 2016
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  12. M Paine

    M Paine Senior Member

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    I was just thinking on the way into work this morning that it's a shame that it's holiday season, and the likelihood of new landmark papers would be slim to none for the rest of the year. How wrong was I!

    Happy Holidays, cheers to one more large step towards a cure.
     
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  13. Simon

    Simon

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    These results look very interesting, especially given the extra findings around PDH regulation. But I'd love to know if the authors have discussed how their findings fit in with the exercise study findings, that generally don't find abnormalities on day 1 of a 2-day maximal exercise test. If there are defects in energy metabolism, you'd expect an maximal exercise test too show them up.

    I think this group also a study that did find abnormal accumulation of lactate on day 1 of a maximal test, but it's not clear how that fits with the normal anaerobic findings on day 1 (measured by gas ratios) of other max tests. Earlier, single maximal exercise tests have mixed findings on lactate levels: some show higher levels, some show normal.

    I've not read the paper so don't know if this has been discussed, but I do think it's important where what should be complementary findings don't seem to quite fit.
     
  14. Ben Howell

    Ben Howell OMF Correspondent

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    Really?

    This is exactly what OMF and Prof. Davis has been doing in his Severely Ill Big Data study.

    I don't believe any pathogen has been found yet, using custom, cutting edge devices. Not just based on titres which are not always reliable.

    What a lot of people seem to be missing is that so far, from multiple studies, it seems to not necessarily matter what the initiating trigger is, the resulting metabolic consequences appear to be the same for patients. The heterogeneity resulting in a homogenous end point. All of the studies so far (Naviaux, Hanson, Armstrong and this one) are all pointing in the same direction.

    We have never had that before, and never with this quality level of research.

    So yes, I do think it is landmark, just as Naviaux's is. They may not offer the answer, but they offer an unprecedented glimpse into the illness that we have never had before.

    Forest for the trees.


    B
     
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  15. MEMum

    MEMum Senior Member

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    My daughter was shown to have autoantibodies to the pyruvate kinase receptors in the basal ganglia.
    Have no idea if this is relevant, and realise PK and PDH have different roles.
    Any ideas more scientifically informed PR members?
     
  16. greeneagledown

    greeneagledown Senior Member

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    whoa
     
  17. Grigor

    Grigor Senior Member

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    It's not only about the end result. It's about recognition as well.

    Large cohort. With the correct criteria. Very important. Makes an impression. Getting more of the medical establishment on board.

    And says a lot about the mechanism of the illness. Many good points. Many.
     
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  18. Ben Howell

    Ben Howell OMF Correspondent

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    Exactly!


    B
     
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  19. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    You seem to misunderstand how progress in science is made.
     
  20. A.B.

    A.B. Senior Member

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    One question to the biochemists here: do recent metabolic studies tell us what diet would be ideal? Should we try to increase consumption of certain nutrients? What's the story with males and amino acids? This study here says that males are breaking down proteins at increased rate in order to make energy. Should malesincrease amino acids in their diet? Whitney seemed to benefit from amino acid supplementation.
     
    Last edited: Dec 22, 2016
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