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Medscape Discusses Fluge and Mella FIndings of PDH Impairement

Never Give Up

Collecting improvements, until there's a cure.
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Great article. It discusses the findings and the bigger study and Anthony Kamaroff brings his critical eye to the findings.

Medscape Medical News

Possible Mechanism Identified for 'Chronic Fatigue Syndrome'

Miriam E. Tucker

January 13, 2017

Blockage of a key metabolic enzyme could explain the profound lack of energy and other symptoms experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), new research suggests.

The findings were published December 22, 2016, in the Journal of Clinical Investigation Insight by Øystein Fluge, MD, from the Department of Oncology and Medical Physics at Haukeland University Hospital, Bergen, Norway, and colleagues.

The study included 200 patients with ME/CFS, as defined by the 2003 Canadian Consensus Criteria, which requires the hallmark symptom of postexertional malaise, among others, to make the diagnosis of ME/CFS. The authors compared serum concentrations of 20 standard amino acids from the 200 patients with ME/CFS and 102 healthy control patients.

In the patients with ME/CFS, there was a specific reduction of amino acids that fuel oxidative metabolism, pointing to functional impairment of pyruvate dehydrogenase (PDH), a key enzyme for the conversion of carbohydrates to energy. Impairment of PDH could result in the cells switching to consumption of alternative fuels, causing a sudden shortage of energy in the muscles and a buildup of lactate, experienced by patients as a burning sensation in their muscles after even minor exertion.

"I think that at present our data are primarily telling us something about the ME/CFS disease. Our findings indicate an impaired function of the PDH enzyme complex, resulting in reduced flux of pyruvate to the [tricarboxylic acid (TCA)] cycle. Increased lactic acid accumulates upon limited exertion, and there is a compensatory use of alternative substrates to fuel the TCA cycle. So, the results indicate an impaired mitochondrial PDH complex function, we believe induced by the immune system," Dr Fluge told Medscape Medical News. Continue reading here.
 
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eljefe19

Senior Member
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I am glad to see this level of detailed research conducted with CFS/ME patients. However, it appears to me that the observed differences in pyruvate dehydrogenase (PDH) mediated respiration between controls and patients was not consistent or large, particularly since some of the significant differences occurred only when female patients were compared separately from male patients.



It does seem likely that there is indeed a problem in that area, e.g., inhibition of the pyruvate pathway to acetyl-CoA in CFS/ME patients, but not with great specificity, since the causes of CRS/ME are most likely not metabolic, but rather immunologic (i.e., due to chronic immune system insult from one or more pathogens, possibly operating on a genetically susceptible individual).



My immediate intuition (well, immediate after spending several hours studying the full research paper published) was that a similar study including a group of chronically ill patients in addition to healthy controls and CFS/ME patients would show similar differences between the generally chronically ill (e.g., cancer, viral chronic, degenerative diseases) and the healthy controls (and likely similarities between the chronically ill and the CFS/ME patients mirroring the results elucidated in the present study).



The transfer of increased rates of mitochondrial respiration by exposure to CFS/ME serum probably reflects the presence of inhibitory factors in the CFS/ME serum (e.g., PDH inibiting PDK1 mRNA, normally seen in advanced starvation where the body is enforcing a direct TCA cycle entry funded by protein breakdown and not permitting gluconeogensis, the latter being inefficient if you are already polysaccharide and lipid depleted in advanced starvation), rather than the underlying proposed (by me) immunogenic pathogen(s).



At minimum though this study should point the way towards clinical tests that could remove the element of subjective judgment by the physician in assessing whether a patient is suffering CFS/ME. In the long run, perhaps this means of identifying CFS/ME patient cellular metabolic dysfunction will permit a finely targeted examination of the specific immune system dysfunction and hopefully pathogens responsible for the disease.

Comment from the medscape article. Any thoughts from anyone?
 

nandixon

Senior Member
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1,092
Comment from the medscape article. Any thoughts from anyone?
My immediate intuition (well, immediate after spending several hours studying the full research paper published) was that a similar study including a group of chronically ill patients in addition to healthy controls and CFS/ME patients would show similar differences between the generally chronically ill (e.g., cancer, viral chronic, degenerative diseases) and the healthy controls (and likely similarities between the chronically ill and the CFS/ME patients mirroring the results elucidated in the present study).
The Fluge & Mella results, when you integrate the metabolic findings with the gene expression findings, are showing that the mTOR (mTORC1) pathway is likely under-activated. This is probably the most important thing to understand, I think.

In most other diseases like cancer, autoimmune diseases (MS, SLE, etc.) and degenerative diseases, mTORC1 seems to be over-activated.

So for the first time we perhaps can see just how different ME/CFS is.

Given that there's a lot of research right now in these other diseases focusing on trying to reduce mTOR/mTORC1 activity, perhaps if those researchers studied ME/CFS they might gain some better insight.
 

eljefe19

Senior Member
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483
@nandixon I've been following your posts judiciously and have built a stack to activate mTorC1. I can explicate the entire stack if anyone's interested. I think Ketamine is the holy grail of mTor. Dr. Goldstein said it was his number one favorite drug for ME/CFS. Will report back. So far, no dramatic results. Still my normal ill feeling.

Edit: Fuck it. So far my stack consists of Phosphaditic Acid, creative hcl and monohydrate, pantethine and pantothenic acid, Leucine and glutamine 2x a day, and high dose Niacinamide for Ceramide production. I want to add the following; Rifampin (possibly upregulates sphingolipids), Ketamine (mTor and AMPA), Florinef (adolosterone and mTor), Sarcosine and/or DXM (mTor), DCA (on the way).
Am I missing anything @nandixon?
 

nandixon

Senior Member
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1,092
@eljefe19

I don't think I would stack anything at the outset. At least initially I would try things one at a time to see what is happening with each supplement. You might be helping things in one way and hurting them in another, and if there's a problem you won't know what's doing what.

And a lot of things that sound good in theory may not work at all or even do the opposite in practice.

Remember too that there is no supplement, vitamin or drug that only does one thing in the body. Everything has dozens or even hundreds of different effects. Various antibiotics, for example, are not just antibiotics but can potentially do many other things. And some are actually best-in-class for these other things. (Rifampin, for example, is stellar at upregulating a particular transporter that may be beneficial in some people and a disaster in others.)

An even if you do find something helpful, a resetting back to homeostasis is a big problem in ME/CFS. Most of us may ultimately need something like rituximab to really help (assuming the current trial has good results)

Personally, I would wait and see what they find and say when you visit OMI.
 

eljefe19

Senior Member
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483
@nandixon thanks for the advice! I definitely do not take a scientific approach. More of a cowboy shotgun approach. I've never had a horror story reaction. Most supps and meds had no perceptible benefit. Oxymatrine being the exception.
 

Snow Leopard

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Comment from the medscape article. Any thoughts from anyone?

The findings of the Fluge/Mela are not the central/specific characteristics of this illness, they are downstream effects, as such, they cannot be used as specific biomarkers. On the other hand, the findings give clues to what is going wrong, when placed in the context of other studies.

The comment ignores the increased SIRT4 expression, which makes things a bit more complicated (since it encourages lipid anabolism). mTORC1 inhibits SIRT4 expression, hence the hypothesis mentioned above.

Some of the specific findings, eg PDK expression (and some other genes that would be predicted given the results) has been replicated in previous studies, eg the Italian twin study currently being discussed in another thread. https://www.ncbi.nlm.nih.gov/pubmed/27676445

Immunologic dysfunction due to gut bacteria, a chronic infection of immune cells (not necessarily B-Cells!) (but insignficant levels elsewhere), or autoimmunity remain popular hypotheses.
 
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eljefe19

Senior Member
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483
Thanks @Snow Leopard. I am still considering immune dysfunction and bacterial translocation, I have entire stacks dedicated to both. However I have only achieved success in certain areas of my health with supplementation. Energy level and PEM are still quite bad, so as the F&M research has been discussed I've added a few things. Your comment on SIRT4 convinced me to get off Lexapro so thank you for that. Do we know of anything that inhibits SIRT4?

@nandixon What transporter were you referring to in regards to Rifampin?
 
Messages
516
So far my stack consists of Phosphaditic Acid, creative hcl and monohydrate, pantethine and pantothenic acid, Leucine and glutamine 2x a day, and high dose Niacinamide for Ceramide production. I want to add the following; Rifampin (possibly upregulates sphingolipids), Ketamine (mTor and AMPA), Florinef (adolosterone and mTor), Sarcosine and/or DXM (mTor), DCA (on the way).

Lots could be said about these, but just a warning to anyone reading about Niacinamide: high doses may completely floor you. That is their effect on me, despite that niacinamide proves time and again to be a part of any combination that benefits me. It inhibits lipolysis and essentially requires a bunch of carbs. This is clearly in conflict with the PDH inhibition. So it's possible it might necessitate high-dose thiamine or that DCA. Simultaneously, for neurotransmitters the (relative) pro-acetylcholine sides of thiamine might be balanced out by the benzo-like effects of niacinamide, such that on paper they seem to complement each other.
 

eljefe19

Senior Member
Messages
483
@Tunguska thanks for the advice! I just ordered allithiamine to take alongside the niacinamide. Do you think I should take niacinamide at night then?