Phoenix Rising: The Gift That Keeps on Giving All Year Long
This holiday season Jody Smith turns her eyes to the people of Phoenix Rising and gives thanks for you all ...
Discuss the article on the Forums.

Elevated Energy Production in Chronic Fatigue Syndrome Patients

Discussion in 'Latest ME/CFS Research' started by A.B., Oct 18, 2016.

  1. RogerBlack

    RogerBlack Senior Member

    Messages:
    857
    Likes:
    2,786
    I have monitored my own glucose levels during PEM, and found them completely normal.
    I idly wonder what very elevated glucose levels would do to PEM, but don't have diabetes.

    Indeed, the recent serum analysis which found all sorts of elevated/depressed metabolites found glucose was completely normal.
    Which is probably a good thing - because if on PEM, the body attempted to ramp up the glucose, bad, bad things may happen, and it might look a lot like diabetes. (though such a large and obvious biomarker might have gotten work done earlier)
     
    Mary, ZeroGravitas and Webdog like this.
  2. Kati

    Kati Patient in training

    Messages:
    5,451
    Likes:
    19,501
    I have not read the paper yet, but here are a few comments:

    1) I am very pleased that new researchers are entering the field. Thank you to the authors for their contribution. i hope they will attend IACFSME.

    2) this is the normal process of science happening before our eyes: scientists publishing a strong paper, qualified as 'landmark', (Naviaux et all) and other scientists verifying the findings and adding more input.

    3) This present paper may not be contradictions to the Naviaux paper- it may in fact be a good compliment to it. However, of course as always, cohort, case definition, cohort size, matters a lot in comparing studies.

    Edit following reading of the paper: they used the 'chronic fatigue initiative' cohort with matched control, patients originating from well known and respected ME experts.

    4) Lastly, indeed, metabolomics and metabolites are very different than the methods used by these authors (though I could be wrong on this point). Both can be quite complimentary to each other in moving further into better knowledge of what is wrong. Perhaps the answer resides in faulty pathways, and perhaps not.

    Personally I am not fixed on any single hypothesis as of what exactly is wrong. But I appreciate scientists and physicians giving a go at discovering the what, who and why.
     
    Last edited: Oct 19, 2016
  3. Chris

    Chris Senior Member

    Messages:
    751
    Likes:
    430
    Victoria, BC
    One quick thought-these patient samples were gathered from top-notch researchers-and therefore not necessarily typical of the average ME patient--they may all have been taking lots of supplements etc to improve their mito performance? But it is puzzling and unexpected, though we can hope for smart researchers to begin providing at least potential answers soonish, I think.
     
    Barry53 likes this.
  4. Barry53

    Barry53 Senior Member

    Messages:
    2,277
    Likes:
    13,685
    UK
    Maybe it is simply a learned "energy craving" habit then, because when my wife is low and and craving energy, even though she knows it will not work, she sometimes (not always) cannot help nibbling chocolate.
     
  5. Barry53

    Barry53 Senior Member

    Messages:
    2,277
    Likes:
    13,685
    UK
    [My bold]

    Presumably they are saying this is a significant indicator of PEM, the body not having recovered from the first day's exercise anything like as much as it should.
     
  6. RogerBlack

    RogerBlack Senior Member

    Messages:
    857
    Likes:
    2,786
    A recent study found CFS patients 18 maximal strength handgrip tests, followed by another test an hour later was positive in that the strength was still down at 1 hour later.

    The actual biochemical causes of the trajectory of PEM will be fascinating to nail down.
     
    Last edited: Oct 18, 2016
    Mary and Barry53 like this.
  7. alex3619

    alex3619 Senior Member

    Messages:
    12,409
    Likes:
    34,771
    Logan, Queensland, Australia
    Its worse than that. The physical capacity actually continues to get worse as shown in the second CPET.

    Energy production tied to glucose uptake might be a big issue. What if post activity our capacity for glucose uptake is in decline? It might take time to recover. Glucose uptake seems to have a ceiling effect in ME if Julia Newton's research is right, but can that ceiling move?

    I often get cravings for foods, not always sweet (usually salty), that cannot be satisfied so are best ignored. Its may not just be a response to low energy, though I think that is a part of it, I think the body can send signals for all sorts of things, but the body appears to be sending contrary signals.
     
  8. RogerBlack

    RogerBlack Senior Member

    Messages:
    857
    Likes:
    2,786
    Ketogenic diet might modulate that significantly.
    In a good, or a bad way, I don't know.
     
    Last edited: Oct 18, 2016
  9. halcyon

    halcyon Senior Member

    Messages:
    2,271
    Likes:
    5,317
    I've been troubled by Ron Davis reporting finding impaired glycolysis because that is opposite of past research that has found increased glycolysis, which this research appears to support. Perhaps one of the important differences between severe and non severe ME?
     
    Kati likes this.
  10. alex3619

    alex3619 Senior Member

    Messages:
    12,409
    Likes:
    34,771
    Logan, Queensland, Australia
    I don't recall offhand the recent enhanced glycolysis research, but I do recall research claiming that from the 90s that I looked very closely at. They presumed enhanced glycolysis, it was inference not fact, and there were alternative explanations. As usual the evidence is more important than the conclusions.
     
    Luther Blissett likes this.
  11. Kati

    Kati Patient in training

    Messages:
    5,451
    Likes:
    19,501
  12. halcyon

    halcyon Senior Member

    Messages:
    2,271
    Likes:
    5,317
    The 90s research I believe is what I was referring to, but I'd have to dig up the references. There is more recent Myhill research that supports it I believe, at least in a percentage of patients.

    From some cursory reading, there appears to be an important intersect between gycolysis, ATP metabolism, and immune cell function, especially in myeloid lineage blood cells. One wonders if this is just yet another signal of increased immune activation in ME.
     
    Luther Blissett likes this.
  13. taniaaust1

    taniaaust1

    Messages:
    11,875
    Likes:
    12,622
    Sth Australia
    I dont tend to crave sugar (no more then I did with before I was sick), in fact I have to get an extremely low carb diet.
     
  14. Marco

    Marco Grrrrrrr!

    Messages:
    2,369
    Likes:
    3,147
    Near Cognac, France
    An interesting finding if replicated.

    What I find frustrating is the lack of discussion. Given that they sought to distinguish between mitochondrial and non-mitochondrial ATP production suggests there may be some physiological significance (apart from suggesting no problem with the mitochondria per se).

    Surely elevated ATP production (presumably derived from elevated glycolysis) has some known physiologcal significance and associated literature?
     
  15. bertiedog

    bertiedog Senior Member

    Messages:
    940
    Likes:
    1,229
    South East England, UK
    But my experience is that although glucose measurements look normal they just don't feel that way so I want to top up every 2 hours in the morning and have a snack within 3 hours of lunch in the afternoon, same thing in the evening. Usually I feel better a short time after eating, it sort of restores energy.

    I am not at all overweight, in fact I am slim so it would seem my need for frequent food is something to do with this illness. I don't do well with much carbohydrate but much better with a mixture of fat and protein so snacks such as nuts are ideal and so is mild cheese with half a no sugar oatcake,

    Pam
     
    Luther Blissett likes this.
  16. ZeroGravitas

    ZeroGravitas

    Messages:
    24
    Likes:
    204
    UK
    Do I understand their method correctly?: Blood samples had been frozen and thawed, monocyte cells separated (and washed?), and incubated for almost 3 days before (further preparations for making) measurements and/or imagining.

    So the measured ATP produced by these cells was produced well outside of the context of patient's bodies? Couldn't this be problematic? From Cort's blog a couple days ago (sorry, not sure of the original references):
    So could it be that after blood borne factors that usually inhibit mitochondrial ATP synthesis (in CFS/ME patients) are removed, it allowed a return to the normal levels of production that were measured? (And having been weighed down, some compensatory configuration(s) then caused ATP overproduction.) Or would 3 days not be enough time to adapt to new environment? Or should the "5% CO2" block metabolic changes? Or am I totally failing to grasp vital aspects of the methodology? (Very likely! I hope I'm not spouting entirely misleading nonsense...?)

    Also, in my previous post, on the Naviaux study, I mentioned that Aubrey de Grey pointed out that mitochondria are continuously being broken down and reconstituted within cells, and my research stemming from that insight indicated that they may last less than 2 days before being recycled (in certain tissues, of mice).
    -----
    This new study apparently contradicts the 2015 Australian metabolomics study (abstract only with full paper here) which claimed to see that:
    [My emphasis.] With increased amino acid use to fuel the citric acid cycle in place of burning carbohydrates (is that synonymous with glucose?). I personally latched on to this study as it showed a raised aspartic acid signature that I'd seen in my own serum amino acids test.
    -----​

    Regarding Naviaux, could it be that there is increased ATP production, but it's is being consumed by (purinergic) signalling, as in his cell danger response (CDR)? I've no idea of the relative quantities of ATP for energy metabolism verses signalling, of any type.
    -----​

    Thanks for linking me to the 2012 Doctor Myhill, Booth, McLaren-Howard study. So that found increased glycolosis in one patient sub-group, the other also having compensatory extra-mitrocondrial ATP production via some different, unknown route:
    But seemingly contradicts the new paper:
    The Dr Myhill paper seemed more involved (on the molecular side), certainly longer and more explanatory. It talks about causes:
    It seems to have looked at neutrophils, as opposed "mononuclear cells" (i.e. lymphocytes and monocytes) in this new study. Would that make a significant difference? I'm not sure about the statistical tools, or how different the practical methods were; I didn't spot the 2012 paper going into as much explicit detail about the Acumen Lab's process, or if their "ability to accurately measure such small concentrations of ATP" should be more/less reliable. (Bu then I didn't manage to read it entirely, let alone hold everything in mind.)

    Both papers evidence increased ATP production in the cell cytosol, which makes for a lot more oxidative damage/stress, of course.

    Thanks and well done if you managed to read this long, undirected post. :)
     
    alex3619, Joh, Wizard and 9 others like this.
  17. Sidereal

    Sidereal Senior Member

    Messages:
    3,086
    Likes:
    17,138
    My understanding of Naviaux's cell danger response hypothesis is that elevated levels of extracellular ATP (which is coming out of damaged/dying cells) is what signals danger to neighbouring cells via its actions on the purinergic receptors.
     
    Hutan, Ben Howell, Valentijn and 3 others like this.
  18. KME

    KME

    Messages:
    90
    Likes:
    537
    Ireland
    Wow, producing all this extra energy sure is exhausting. I can’t pretend to understand this paper now, but I suspect that together with other papers like Naviaux’s, it’s going to propel the field forward. One thing the papers seem to agree on is that there is significant variability between patients, and that treatment will likely need to be tailored rather than one-size-fits-all.

    The Lawson et al findings made me think of a comment I came across recently that ME/CFS is like having your foot to the floor on both the accelerator and the brake at the same time. It captured my imagination so much that I promptly forgot where I saw it, who said it, and even if it was specifically about ME/CFS, so apologies for no reference. But the experience of feeling wired (accelerator) and tired (brake) is familiar to me.

    The Lawson et al findings also makes me think of some random abnormal phosphate findings on blood tests that always made me wonder what was happening ATP-wise – sometimes elevated phosphate, sometimes decreased phosphate, with no dietary explanation, and consistently low energy. I haven't seen abnormal phosphate mentioned in the literature but maybe it's buried in there somehwere.

    I think @alex3619’s comment that we may accumulate ATP because we cannot use it is a very interesting alternative interpretation – I hope this will be explored. I could well believe that our cells could still contain a backlog of ATP we’ve managed to create but haven’t been able to access. Like the difference between a nice, accessible debit/checking/current account and one of those locked-away-for-years savings accounts. On paper we look wealthy, but in reality we don’t have money for food. Figuratively speaking.

    In seeking to understand glycolysis, I came across the following explanation https://www.khanacademy.org/science...tion-and-fermentation/glycolysis/a/glycolysis, and in a Q&A underneath, this stuck out:

    “If oxygen is present pyruvate goes to be processed by the Mitochondria resulting in the greater production of ATP (about 36 ATP per glucose molecule) and when no oxygen is present the pyruvate undergoes a VERY inefficient method of producing ATP outside the mitochondria known as fermentation (yielding about a measly 2 ATP per glucose molecule).”


    It also stuck out that glycolysis was described as an “ancient metabolic pathway” – reminded me of dauer.

    And this answer reminded me of @Barry53’s comments above re heat:

    “There are multiple things that phosphates aid during glycolysis. First by phosphorylating glucose in the first step to glucose-6-phosphate this allows for the diffusion of more glucose molecules into the cell since molecules move down their concentration gradient and by putting a phosphate group on glucose it changes the molecule enough to enable glucose to move into cells without the aid of energy or down it's [sic] concentration gradient. Secondly it's [sic] importance has to do with the energy or thermodynamics of the breaking down of glucose. By taking the energy gained from breaking down glucose and using it to phosphorylate ADP to ATP the cells can harvest this energy to be used latter in other metabolic reactions. If this didn't occur the cell would loose [sic] all of the energy as heat, think of a fire. Wood is a polymer of glucose molecules and fire breaks apart these molecules, which produces a lot of energy, but in this reaction it is dissipated as heat, where in the cell by using phosphate it allows cells to harvest the energy from the break down (catabolism) of glucose.”


    I also second @ZeroGravitas’s querying how methodology might affect findings, and am similarly unsure of the validity of my querying. Could the problem be the feedback mechanisms to the mitochondria/cells, in the same way that we may have faulty cell danger signalling? It seems that the context is important; our bodies seem to have created an environment where things look fine but don’t function well at all.


    I’m looking forward to seeing this research mushroom over the next few years. This paper, along with other recent papers in the area, will hopefully cause an explosion of questions and studies...
     
  19. halcyon

    halcyon Senior Member

    Messages:
    2,271
    Likes:
    5,317
    Low serum phosphate is mentioned in the grey literature, but I don't believe it's been found (maybe not even looked for?) in any published research. I've had this as well, intermittent low serum phosphate with no other reasonable explanation.
     
    KME likes this.
  20. Sidereal

    Sidereal Senior Member

    Messages:
    3,086
    Likes:
    17,138
    Helen, Mary, Luther Blissett and 3 others like this.

See more popular forum discussions.

Share This Page