Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[nandixon]

There's an interesting relationship that's been found between increased SIRT4 and cellular senescence. In this case, the microRNA, miR-15b, appears to be involved in downregulating SIRT4. (2016 reference) (Just looking for potential autoantibody targets upstream of what Fluge & Mella found.)

 

[nandixon]

Also, it would be nice if Fluge & Mella could confirm their mRNA expression findings by measuring the actual corresponding protein (enzyme) products, since there's not always a good correlation between increases/decreases in mRNA and the amount of translated protein. (I'd like to verify that we're really taking a double hit to both the E1 and E2 subunits of the PDH complex by an increase in the PDKs and SIRT4, respectively.) Everything they've presented seems to fit pretty well, though, and this may be the best investigative study for ME/CFS that's been done so far.

 

[Murph]

Hi! This is my first post. I've joined after getting a lot of value from reading these forums without having an account over the last couple of months. So many very clever people, and such a positive community!

I wanted to make my inaugural post in this thread in order to add a tiny sliver of anecdote to the discussion that some may find useful. I've been a patient at CFS Discovery, the clinic run by Dr Lewis in Melbourne, Australia. (He's co-author on some of those metabolic papers by @ChrisArmstrong, et al.)

I was out at his clinic a few weeks ago (prior to this Fluge, Mella paper dropping, but I now suspect he was well aware of its contents) and he encouraged me to add amino acids to my diet, in the form of whey powder.

I bought the brand he recommended (which I shan't name here in my first post for fear of appearing to be a shill!) and have been consuming it each day since.

I keep a health diary which shows improvement over that period, although I am aware that this time of year is unusual and so not a great time for drawing definitive conclusions from data.

What I found interesting is that two of the most abundant AAs in the mix are the two ketogenic amino acids being discussed above: Lysine and Leucine. It also contains smaller amounts of several of the other "Category II" acids that Fluge et al indicate feed into production of Acetyl-CoA downstream of the hypothesised PDH obstruction.

The take-away message I guess, is that at least one respected physician suspects amino acid supplementation may be beneficial, and at least one patient has tried it (however briefly) with at least some possible upside.

(n.b. I avoid dairy. At first I avoided it because I learned casein may be an immunological trigger. And now I can't tolerate it digestively. Whey powder is casein free, however, and the one I have been taking has been very easy on the stomach.)

 

[Sasha]

Hi @Murph, and welcome to the forums!

Thanks for posting about your treatment. As a very longstanding member of Phoenix Rising (in fact, I think I hold the record for the biggest number of posts ) I'm going to say that I'm sure you're not a shill and I wonder if you'd mind saying what brand the whey powder supplement is that you're taking, if that's OK with you. If you were a shill I think you'd have written a very different message from the considerate and cautious one that you did in fact write.

I'd been wondering when/if specialist ME/CFS clinicians would start trying to treat with amino acids in the face of the metabolomics work that's been coming out, and it's very interesting to hear about your experience.

I'm no biologist and need to mug up on this stuff but I was wondering what dose of the whey powder you're on and whether you've been advised to lower your intake of carbs, and to add in other supplements to support ketosis. I get the impression from my superficial scanning of this thread that with ketogenic diets, people load up on protein and reduce carbs to sort of flick a metabolic switch that makes their body use amino acids preferentially as fuel (ketosis), and that amino acid supplementation at lower levels doesn't have that effect.

Is that the purpose of this supplementation, as far as you're aware? To put you into ketosis?

Thanks again for the interesting information, and sorry to bombard you with questions!

 

[alex3619]

It's worse than that: it takes 3 times more energy to convert lactate back to glucose

Which might easily qualify as a vicious cycle, though in this case not uncoupling but pathophysiology-induced. How much energy do we waste converting lactate to glucose if we are doing it a lot, all the time, and especially if in PEM? Its a drain on total body energy. It will impact the liver. I am still unclear as to details.

 

[Sasha]

Actually, I'm wondering whether there are likely to be benefits of supplementing with amino acids but below the level where you'd go into ketosis.

 

[alex3619]

Actually, I'm wondering whether there are likely to be benefits of supplementing with amino acids but below the level where you'd go into ketosis.

This is the approach which I see as most likely helpful for most of us. As for aminos, unless there is specific need I would keep it simple and say protein, there are too many involved. There are too many questions unanswered in the science right now, in a year I think we might have a clearer picture to start formulating really promising ideas.

 

[Sasha]

This is the approach which I see as most likely helpful for most of us. As for aminos, unless there is specific need I would keep it simple and say protein, there are too many involved. There are too many questions unanswered in the science right now, in a year I think we might have a clearer picture to start formulating really promising ideas.

I seem to remember @Rose49 saying that Whitney used to eat amino acids (i.e. as supplements), even though they tasted horrible, because they were the only thing that gave him any energy. I wonder if that was better for him than normal protein-rich foods, and if so, why?

Interesting that @Murph's doctor is also recommending a supplement (whey powder), rather than increasing protein in the diet. Again, I wonder why?

 

[alex3619]

wonder if that was better for him than normal protein-rich foods, and if so, why?

If digestion is sufficiently compromised then individual aas will help. So would digestion supplements, such as digestion enzymes.

 

[alex3619]

(whey powder)

I would like to know if its cold processed or pasteurized. In either case it will be a very good source of quality protein. If its cold processed it may boost glutathione synthesis.

 

[Marco]

Just wondering if these metabolic findings are supported by population data suggesting a small but significant association between ME/CFS and the incidence of certain types of lymphoma :

An observation that may support a variant of an autoimmune mechanism underlying the entity is a moderate but highly significant increase in risk of B-cell lymphomas in elderly CFS patients, indicating a chronically activated B-cell system [23]. In this population-based case-control study among almost 1.2 million cancer cases aged more than 65 years, and 100.000 elderly controls without cancer, with a prevalence of CFS 0.5% in both groups, a modest but highly significant association between CFS and non-Hodgkin lymphoma was reported. There were no significant associations to other cancer types when adjusting for multiple comparisons. Of lymphoma subtypes, a significant association to the most common aggressive lymphoma (diffuse large B-cell lymphoma) was reported. Interestingly, there was a highly significant association between CFS and marginal-zone lymphomas [23]. This low-grade B-cell lymphoma type often arise in extra-nodal tissues, in which chronic stimulation by an antigen is thought to play an essential role in lymphomagenesis either from chronic infections or from autoimmunity [24].

I also wonder if Fluge/Mella's original patients had particularly aggressive lymphomas?

 

[Gijs]

These hypo metabolic findings from Fluge or Naviaux will not be solved with a simply diet or any supplements. Especially when there are antibodies involved or an ongoing unknown disease proces.

 

[Tuha]

These hypo metabolic findings from Fluge or Naviaux will not be solved with a simply diet or any supplements. Especially when there are antibodies involved or an ongoing unknown disease proces.

I think nobody is saying that diet or supplements will solve everything but it can work for someone. There are many patients who got some benefits form diet. I have the same experiences. I put more proteins and less carbs into my diet and got already after few days more energy (20 % increase). I have still a lot of difficulties, I have to rest a lot but it had definitly a very positive effect on the quality of my life. I think we will know soon where these metabolic findings lead.

 

[Undisclosed]

I am not sure why you write they are looking to get to a cause or treatment or rule out certain things.

this was my criticism - there is no info that they did that.
at least i can find it nor did lipkin reply with that info to my email.

if you know, what parasites/pathogens the study participants of
- the naviaux study have been tested based on the findings or if you have that info from
- the fluge/mella study or if you have that info from
- the lipkin study, please post that.

i'm most interested in this info.
and i believe - others, are looking for progress are too.

The following are not constructive criticisms, nor are they helpful:

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

iits old news.
it leads to nothing. zilch.

they may be just desperate in explaining their rituximab.

they have no clue and dont know what they are doing.
such sort of "research" just underlines that.
its aweful. scaring. horror. for us.

its imo a dead end.

we dont have a special or new disease.
we are victims of their stupidity and ignorance.

You can ask Fluge and Mella why they didn't test for parasites -- it's simple they are not doing a pathogen study -- this study involves metabolic profiling. If it wasn't for them, we wouldn't know that Rixtuximab may be a possible treatment for at least a sub-group of patients and we have learned of possible involvement of mechanisms via their metabolic profiling. The research is moving forward in a very important way. It's not the end when they discover metabolic differences -- others can replicate and then the reason why can be researched. Because the human body is so complex, we might never have a reason and still have a treatment. I have been to 2 InvestInME conferences which presents most excellent research and parasites have not been mentioned -- must be a reason why -- most of us get it.

This is supposed to be a discussion related to research which has nothing to do with parasites, so unless you have something to contribute related to impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS then I suggest you go start a thread about parasites and ME/CFS.

 

[Sasha]

These hypo metabolic findings from Fluge or Naviaux will not be solved with a simply diet or any supplements. Especially when there are antibodies involved or an ongoing unknown disease proces.

ME/CFS may well not be curable with supplements but perhaps it's possible that supplements can help a bit. I'm pretty much housebound now and have been for years. If I can improve enough to be able to sit up two hours instead of one hour, my quality of life would improve tremendously.

Let's not dismiss things that might help, even if they don't cure!

 

[Hip]

Its a drain on total body energy. It will impact the liver. I am still unclear as to details.

Yes, as you say, the liver's role (via the Cori cycle) in clearing up the extra lactic acid produced in the muscles and other organs in ME/CFS will be a drain on total body energy, but I am guessing that this energy drain might simply be addressed just by eating a bit more energy-containing food, to fuel the liver's increased energy needs.

Although if running the Cori cycle is a drain on the local cellular energy supply to the liver cells, then conceivably that might slow other liver functions down a bit, such as the detoxification process (which might then worsen PEM, if the ME/CFS patient has a high toxic load for any reason, eg from mycotoxins). But I am not sure if it really works that way: ie, whether or not the Cori cycle does drain energy from other liver functions.

Note though that the way the liver works in ME/CFS patients might be a bit different to its functioning in healthy people: if the mitochondria and energy metabolism of liver cells in ME/CFS patients is also be defective, then it's going to be more of a struggle for the liver cells to create the ATP energy necessary process the lactic acid. So finding the cellular energy to run the Cori cycle might present more problems for ME/CFS patients.


Apparently the kidneys and skeletal muscles are also involved in clearing lactic acid; the liver does the bulk of the work (up to 70%), but the kidneys may do as much as 30% of the work.

 

[alex3619]

SIRT4 inhibits fatty acid oxidation

So that leaves protein, and implies that to assist a patient for energy, if that is a good idea, a broad range of aminos without higher fat intake might be indicated. In other words, not the typical ketogenic diet, but something different. Low fat protein sources plus low energy vegetables is looking promising. A typical example would be an egg white omelette that is loaded with high nutrient low energy vegetables. Or grilled fish and salad, etc. I would add some high polyunsaturated nuts for essential fats though, unless lean meat is the protein source in which case there should be enough ... maybe.

I hope we see some formal studies soon. I also hope we start looking at the inhibiting factors, and back-tracking them to the source. Who wants to bet on B cells? (Rhetorical question.)

 

[Rossy191276]

Yes, as you say, the liver's role (via the Cori cycle) in clearing up the extra lactic acid produced in the muscles and other organs in ME/CFS will be a drain on total body energy, but I am guessing that this energy drain might simply be addressed just by eating a bit more energy-containing food, to fuel the liver's increased energy needs.

Although if running the Cori cycle is a drain on the local cellular energy supply to the liver cells, then conceivably that might slow other liver functions down a bit, such as the detoxification process (which might then worsen PEM, if the ME/CFS patient has a high toxic load for any reason, eg from mycotoxins). But I am not sure if it really works that way: ie, whether or not the Cori cycle does drain energy from other liver functions.

Note though that the way the liver works in ME/CFS patients might be a bit different to its functioning in healthy people: if the mitochondria and energy metabolism of liver cells in ME/CFS patients is also be defective, then it's going to be more of a struggle for the liver cells to create the ATP energy necessary process the lactic acid.


Apparently the kidneys and skeletal muscles are also involved in clearing lactic acid; the liver does the bulk of the work (up to 70%), but the kidneys may do as much as 30% of the work.

Thanks for these thoughts Hip...Your hypothesis aligns with some of my results...One of the first things doctors found in me was low transferrin, very high transferrin saturation, and later high ferritin... They explained transferrin is made in the liver...Later I also found something else (name escapes me at moment) that doctor said was made in liver to be very low as well...

Doctors have never had an explanation for the deficiency of these things made in liver and have suggested high ferritin is part of inflammatory response...

Is it common for people to have low transferrin in me/cfs...If so, this I would things supports idea that the process you talk of is affecting liver functions...

I would also like to add my own experience so far as a case study which supports the idea that researchers are very much on the right track with all that has been talked about in this thread...

I got suddenly very sick with what I now understand to be me/cfs a little over a year ago... Within a couple of weeks with the usual story of being so sick in hospital but doctors saying there was nothing wrong I started to try to increase activity with devastating effects (rather than pen I call it PES- post extensional shutdown) where my body would go into complete shutdowns).. I learned very quickly that physical exertion made me very sick... By chance I began eating what I would describe as a very healthy diet after I got out of hospital (low sugar, quite low carbs, lots of veggies, healthy meats)...around the same time I got an incredible appetite-- I still have recordings where I literally started to need to eat twice as much as usual-- because I couldn't keep up with demands I added a meal replacements high in protein and amino acids etc twice a day as well as heaps of other 'healthy' food...Within another 3 weeks I started feeling much better rally quickly (went from being apartment bound to walking 500 metres in a week)... I continued to get better to the point where early this year I felt completely healthy again and started getting back to full activity running, playing tennis, etc... I also went back to old diet...I felt completely healthy again but in March I was playing tennis and I literally felt my body 'switch' into me/cfs mode where I new within 5 secs I had some of the feelings back...With still no diagnosis I tried to continue to do activity over the next coulee of weeks until I had a complete shutdown and since then I have been mostly bed bound/housebound but now can go outside in wheelchair...

In looking back my guess is that during the initial stages of the disease my body made an attempt to get well by creating this incredible appetite and by chance I stumbled on the correct mix of diet, supplements, and physical rest that actually got me symptom free for a short time...Unfortunately I didn't realise I still had the vulnerability and now that I have been sick again for nearly a year I imagine it is much harder to get the body to switch back...

Thanks to everyone who contributes to these forums...I am continuing to communicate often with my doctor who is very close with the research group in Australia and I firmly believe the discussions here will play a key role in the eventual treatment options...

 

[CFS_for_19_years]

I bought the brand he recommended (which I shan't name here in my first post for fear of appearing to be a shill!) and have been consuming it each day since.

I'm eager to hear what brand you're using. I don't think anyone thinks you're a shill.

Oh and welcome Great first post!

 

[hixxy]

@Sasha Early on in this disease I had benefits from amino acid powder, but the effect diminished over a month or two, so it was another thing I crossed off the list. Right now I get 80g of hydrolyzed whey protein per day in enteral feeding formula which is the next closest thing to free amino acids and get no energy improvements from it either.