Possible Mechanism Identified for 'Chronic Fatigue Syndrome'

J William M Tweedie

Well-Known Member
More progress!
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.
The model, if correct, has implications for prescribing exercise for patients with ME/CFS. "Based on the findings in the study, we can understand why patients need to stay at rest, minimizing the energy deficiency and reducing the symptoms caused by lactic acid accumulation.... The value of doing exercise should, however, not be underestimated, and the level of activity tolerated will depend on the severity of the disease," Dr Fluge said.
He added, "An ME/CFS patient's ability to handle exercise is very individual. Generally, I think the physicians should listen carefully to the patients, and find the optimal activity level through pacing, to avoid 'crashing' with the resulting major symptom increase that can last for weeks and months."
Asked to comment, Anthony L. Komaroff, MD, professor of medicine at Harvard University, Boston, Massachusetts, and editor-in-chief of the Harvard Health Letter, told Medscape Medical News, "This is the latest of many research studies that are pursuing a simple idea: That the human being who says 'I don't have enough energy' could have a problem with their cells producing enough energy.... It adds to a large literature indicating that cellular energy metabolism is abnormal in patients with ME/CFS."
However, he cautioned that the investigators inferred the abnormality in PDH, rather than directly measuring it, and that although "[t]heir argument seems plausible...I wouldn't be convinced until a second study by other investigators, studying other patients with ME/CFS, confirmed this." Continue Reading
 

Paw

Well-Known Member
Sort of like a slow-motion form of Leigh's disease? Which, I see, is treated by Alpha Lipoic Acid, ALCAR, and, most importantly, large doses of B1.
 

GG

Well-Known Member
How about breaking up that post, to make it easier to read? Thanks :)

GG
 

Not dead yet!

Well-Known Member
I've been reading a lot about biotin lately and many of the key phrases and medical terms in that study made me think of it. Pyruvate and anything carboxylate makes me think of biotin. I'm up to 10 grams now (I had a headache, so I'm upping it slowly with initial goal of 100 grams). It's hard to say whether a recent med change or the biotin is doing it, but I'm able to do light housework again. I haven't read that article yet, thank you for pointing it out. I'm planning a visit to the med library locally and I might just use that one in my ongoing investigations.

Oops, I just clicked through and it gave me a login required message with your name filled in :) I guess I'll google it. Found it no worries, had to click the "published" link.
 
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Not dead yet!

Well-Known Member
Oops can't edit that one anymore. Ok so I'm only on page 2 of the study, but already I'm hearing bells ringing... AMPK is the final, last step of catabolism, when an athlete has pushed themselves far far beyond their abilities (like during a track meet), they form AMPK and they "crash." Then a process of normalization sets in and in 3-4 days they can go back to their training. Both my parents were pro athletes. I'm familiar with pyruvate/AMPK in general. pyruvate controls something athletes call "VO2 Max" basically how long you can keep up a pace before you collapse. ("Hitting the Wall")

So to put it into laymen's terms, abnormal AMPK activation means your body thinks it has just run a marathon. And if pyruvate is being shunted away from doing useful work, then your endurance will be very low. Well, we knew that, it just wasn't shown by chemistry yet. This is a very cool article.

When you've used up all your pyruvate in almost all your cells, AMPK is formed to give the body the message that it's time to stop, and to leave a message for the body to repair itself STRONGER and with more ENDURANCE next time. For some reason in this situation, the message to make the body stronger and have more endurance next time isn't getting through. Ask any pro athlete and they can tell you they have to work out to exhaustion to become better athletes, they may even know what AMPK is and what it does for them.
 

Abrin

Well-Known Member
I've been reading a lot about biotin lately and many of the key phrases and medical terms in that study made me think of it. Pyruvate and anything carboxylate makes me think of biotin. I'm up to 10 grams now (I had a headache, so I'm upping it slowly with initial goal of 100 grams). It's hard to say whether a recent med change or the biotin is doing it, but I'm able to do light housework again. I haven't read that article yet, thank you for pointing it out. I'm planning a visit to the med library locally and I might just use that one in my ongoing investigations.

Oops, I just clicked through and it gave me a login required message with your name filled in :) I guess I'll google it. Found it no worries, had to click the "published" link.

How interesting! I had just finished reading an article that mentioned biotin just before reading your post.
Davis said that his son Whitney showed errors in B-vitamin metabolism, resulting in a very rare deficiency of biotin; this is important, because enzymes in the citric acid cycle are dependent on biotin. In another patient, tryptophan metabolism was a problem.
http://www.meaction.net/2016/06/04/ron-davis-errors-metabolism/

Maybe when I come into some money again I'll look into trying it as well. :)
 

Not dead yet!

Well-Known Member
I'm looking at this as one of the multifaceted plans I have for keeping the damage to a minimum until the health policy people stop having reactive catatonia whenever they think of ME/CFS. Someday they'll have to work on it. But I may be dead by then. I'm still tweaking the plan, but one of the goals is to discourage biofilm formation so that secondary infections have to work harder to stay hidden.
 

Learner

Active Member
Though there are subsets of CFS patients, I think there's at least one that a multifaceted approach will work, possibly because the cause was multifaceted.

Something like: infection(s) damage cells and steal nutrients. Biofilms develop, protecting infections. Mitochondria get damaged by infections and drugs used to treat infections. All on top a body with lesser ability to fight, with existing toxicity and lessened ability to get rid of them due to genetic factors. Tipping point is reached and CFS ensues.

Unwinding all of this will take a multifaceted treatment plan.

Or maybe there's a magic pill. But somehow, I doubt it.
 

Not dead yet!

Well-Known Member
Meanwhile over in the tinnitus forum, they are also discussing pyruvate and too much lactic acid: https://www.tinnitustalk.com/thread...te-tpp-stopped-my-tinnitus.13673/#post-183877

My path to that article started by researching beriberi symptoms, and then looking to see if there is a TPP supplement available. I did suffer childhood malnutrition and muscle wasting until my situation improved after age 10. If I'm not careful with my diet even now, the symptoms seem very quick to return. It's not the entire problem with my health, but it can confuse matters.

I wonder if anyone's tried to connect thiamine to ME/CFS before. This kind of thing makes me wonder how many factors there are in the decision of pyruvate to go to the citric acid cycle or lactic acid cycle. And whether those two are the only options, or if that's even the right question to ask. I'm not sure anyone fully understands the human metabolism. There is a UCLA professor who swears that lactic acid is a good thing and his data is sincere enough. But if the big brains can't figure it out, what hope do I have? What if the right question is actually, "why does a sick body use lactic acid poorly?"

http://newsroom.ucla.edu/releases/UCLA-Study-Challenges-Conventional-7834

Edit: There's more too: https://www.muhadharaty.com/files/lectures/016/file16593.pdf

"Histotoxic hypoxia: because of the action of certain toxic agents, the tissue cells cannot make use of the O2 supplied to them such as in cyanide poisoning, in which the action of cytochrome oxidase
(respiratory chain enzyme in the mitochondria) is completely blocked. Also, deficiency of oxidative enzymes such as vitamin B[1] deficiency (Beriberi)." Emphasis is mine.

Until stumbling on that, I didn't realize that beriberi had a hypoxia effect.
 
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Paw

Well-Known Member
What if the right question is actually, "why does a sick body use lactic acid poorly?"
Yes! This is such an important point, I think. And there are countless analogous questions that should be formulated the same way.

It's so easy to get misdirected with wild goose chases about reactions to all sorts of specific substances, receptors, transmitters, etc -- whereas the core problem may lie elsewhere (and may be very different from person to person). I'm not saying these are mis-investigations, just that it's good to be aware of the possibility of tunnel vision.
 

Learner

Active Member
Our bodies need a lot of nutrients, and they need to be in balance, so there are adequate cofactors to make biochemical processes work.

One supplement can't be the Holy Grail. Naviaux's metabolomics paper says though patients have many similar abnormalities, for the most part, we differ and have our own unique imbalances.

Many nutrients do more than one thing in the body, so they can be overused in one process that's working overtime, resulting in a shortage elsewhere... I have the most experience with B6, but there are numerous examples, including B1.

I wonder if anyone's tried to connect thiamine to ME/CFS before.

https://www.healthrising.org/blog/2...gia-mecfs-found-early-reports-spark-interest/

My doctor has me taking 650mg of benfotiamine, mainly to support my transsulfuration pathway, but also to support my Krebs cycle. It has helped.

Reading your posts and all the link makes me think about oxygen being a cofactor.

My doctor has me doing hyperbaric oxygen therapy (HBOT), which brings more oxygen into my body. I sleep amazingly well in the HBOT chamber, and feel refreshed aftereards, and overall I've improved since starting it in January.
 

Issie

Well-Known Member
Our bodies need a lot of nutrients, and they need to be in balance, so there are adequate cofactors to make biochemical processes work.

One supplement can't be the Holy Grail. Naviaux's metabolomics paper says though patients have many similar abnormalities, for the most part, we differ and have our own unique imbalances.

Many nutrients do more than one thing in the body, so they can be overused in one process that's working overtime, resulting in a shortage elsewhere... I have the most experience with B6, but there are numerous examples, including B1.



https://www.healthrising.org/blog/2...gia-mecfs-found-early-reports-spark-interest/

My doctor has me taking 650mg of benfotiamine, mainly to support my transsulfuration pathway, but also to support my Krebs cycle. It has helped.

Reading your posts and all the link makes me think about oxygen being a cofactor.

My doctor has me doing hyperbaric oxygen therapy (HBOT), which brings more oxygen into my body. I sleep amazingly well in the HBOT chamber, and feel refreshed aftereards, and overall I've improved since starting it in January.
Many of us POTSies have connected B1 as a need. Here is any old thread about it on another forum I have participated in.
http://www.dinet.org/forums/topic/2...tamates-heavy-metals-epigenetics/?hl=thiamine

Issie
 

Creekside

Well-Known Member
A subset of us don't suffer from physical limitations from ME. Even when my brainfog and mental lethargy were severe, my legs were capable of a 40 km bike ride or whatever else my muscles could do when I was healthy. I think the 'low energy' symptoms are downstream of ME's core dysfunction, which I believe is in the brain.
 

Learner

Active Member
A subset of us don't suffer from physical limitations from ME. Even when my brainfog and mental lethargy were severe, my legs were capable of a 40 km bike ride or whatever else my muscles could do when I was healthy. I think the 'low energy' symptoms are downstream of ME's core dysfunction, which I believe is in the brain.
That doesn't sound like classic ME/CFS at all. Not that you weren't sick.

My brain fog has disappeared with treating viruses, working on gut microbiome and being replete in B vitamin B's, antioxidants, hormones, amino acids and lipids. And treating autoimmune antibodies, MCAS and POTS. I still have trouble with aerobic exercise, however.
 

Creekside

Well-Known Member
That doesn't sound like classic ME/CFS at all.

No, I agree that it's hardly 'classic', which is why I said it's a subset. I did read several other people's reports of similar lack of physical limitations. At least one was doing fairly extreme bodybuilding. He had no problems continuing that level of physical exertion, but he did suffer from brainfog and other ME symptoms.

I've tried lots of treatments, but still haven't found anything to reliably affect my brainfog.
 

Learner

Active Member
No, I agree that it's hardly 'classic', which is why I said it's a subset. I did read several other people's reports of similar lack of physical limitations. At least one was doing fairly extreme bodybuilding. He had no problems continuing that level of physical exertion, but he did suffer from brainfog and other ME symptoms.

I've tried lots of treatments, but still haven't found anything to reliably affect my brainfog.
Again, it doesn't sound like what you have is ME/CFS. However, ME/CFS seems to be some combination of different problems, including viruses, autoimmunity, immunodeficiency, and nutrient and hormone deficiencies. Testing can help determine what's going on. It's also a disease of mitochondrial dysfunction, which makes energy for exercise.
 

Creekside

Well-Known Member
Again, it doesn't sound like what you have is ME/CFS.

I fit the criteria for ME. I most definitely had PEM. I had a lot of tests for other possibilities, but nothing abnormal was found.

It's also a disease of mitochondrial dysfunction, which makes energy for exercise.

No, mitochondrial dysfunction might be a common symptom, but there's no evidence that it's a core part of the disease. Many of us don't have any signs of mitochondrial dysfunction or lack muscle endurance, while having other symptoms common to ME. It's simply a disease with widely varying downstream effects, and widely varying upstream sensitivities too.

Until we get a reliable test for ME, there's no way to be sure whether someone does or doesn't have whatever is the core problem.
 

Learner

Active Member
I fit the criteria for ME. I most definitely had PEM. I had a lot of tests for other possibilities, but nothing abnormal was found.



No, mitochondrial dysfunction might be a common symptom, but there's no evidence that it's a core part of the disease. Many of us don't have any signs of mitochondrial dysfunction or lack muscle endurance, while having other symptoms common to ME. It's simply a disease with widely varying downstream effects, and widely varying upstream sensitivities too.

Until we get a reliable test for ME, there's no way to be sure whether someone does or doesn't have whatever is the core problem.
I know many people with ME/CFS. They have a number of different problems causing their illness, no two exactly the same, due to DIFFERENT genetics and environmental factors.

ME/CFS is just a list of symptoms - real medical things cause them. Here are the diagnostic criteria for which #1, which is required is an impairment of activity levels:

Screenshot_20220314-180151.png


And, the research is indeed showing mitochondrial dysfunction:

"ME/CFS Metabolomic Study Points to a Potential Cause of Mitochondrial Dysfunction - Health Rising" https://www.healthrising.org/blog/2...drial-dysregulation-chronic-fatigue-syndrome/

"An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients - PubMed" https://pubmed.ncbi.nlm.nih.gov/32041178/

"The "Starvation" Disease? Metabolomics Meets Chronic Fatigue Syndrome Down Under - Health Rising" https://www.healthrising.org/blog/2...hronic-fatigue-syndrome-starvation-australia/
 

Creekside

Well-Known Member
And, the research is indeed showing mitochondrial dysfunction:

There's some data showing that some PWME have mitochondrial dysfunction, but I haven't heard anything to indicate that it applies to the majority of PWME. If a significant percentage of us don't show that sort of dysfunction, then it's not a core part of ME, it's just a downstream problem that some people have.
 

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