New Fluge & Mellas new metabolic profiling study

Seanko

Well-Known Member
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome


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.
 
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Seanko

Well-Known Member
There is a layperson's summary available here
http://kavlifondet.no/2016/12/new-study-on-pathological-mechanisms-in-me-from-bergen-research-group/

New study on pathological mechanisms in ME from Bergen research group


English22. DECEMBER 2016
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
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.

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 (http://kavlifondet.no/2016/12/new-study-on-pathological-mechanisms-in-me-from-bergen-research-group/#_edn1, [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.


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://kavlifondet.no/2016/12/new-study-on-pathological-mechanisms-in-me-from-bergen-research-group/#_ednref1 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
 

Gijs

Active Member
No. it is not so big as it looks. Also it must be replicated first. But at this moment there is a metabolic hype. There is no consistent finding or profile. The only thing is that there is a hypometabolic state in CFS patiënts which you can expect in any disease.
 

ElisaB

Member
I think this is likely a huge study. This fits with most me/cfs symptoms. It could me "it"

My blood work mirrors their findings regarding. 3-methylhistadine. I had this done on a Doctors Data Amino Acid profile through Dr. Amy Yasko. My level was more than double the highest normal.

Doctors Data and Dr Amy point to B12 and methylfolAte to address this abnormality. How does methylfolate gene/snips play into this?

Please check your blood work for amino acid analysis via Doctors Data or other lab and post back here...
 

Remy

Administrator
Treatment of pyruvate dehydrogenase deficiency disease includes many of the supplements some of us have found useful like carnitine and thiamine.

I also see dichloroacetate mentioned...Naviaux also did a study using DCA and it's used in some alt cancer programs.

The Naviaux study found just under 50% improved, 30% had no change and 20% worsened on the DCA. It does seem to have some significant side effects, mainly peripheral neuropathy, that seem to be dose dependent and reversible. However, apparently Naviaux said he would not recommend it as a treatment due to the side effects. I would love to hear more about this because anything that can help half of the people seems worth a brief trial for tolerability to me.

http://emedicine.medscape.com/article/948360-treatment#d7

https://www.ncbi.nlm.nih.gov/m/pubmed/16725381/
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
@Cort & @Rachel Riggs is this as big as I think it is? :)
Not having much experience with this subject I still think its really good...The one question mark - why did the cells in the ME/CFS patients serum use more oxygen not less than the cells in the healthy peoples serum? That sounds like they were more energetic but I don't know if cellular respiration is a marker for energy.

I'm working on the blog now.
 

Anomie

Active Member
Not having much experience with this subject I still think its really good...The one question mark - why did the cells in the ME/CFS patients serum use more oxygen not less than the cells in the healthy peoples serum? That sounds like they were more energetic but I don't know if cellular respiration is a marker for energy.

I'm working on the blog now.
YES!
 

Seanko

Well-Known Member
On Facebook group, @Rachel Riggs posted a reply she got from Dr Robert Naviaux. :)
PDH = pyruvate dehydrogenase

"PDH is a mitochondrial enzyme I’ve studied for over 20 years. It is part of the
cell danger response (CDR). It is part of the coordinated, multienzyme,
multipathway response to environmental stress that is called dauer that we published
on in PNAS. We have even done clinical trials with a drug called DCA
(dichloroacetate) that activate PDH in mitochondrial disease (PMID 11410919), but
the toxicity of PDH activation outweighed the benefits.


PDH is part of the orchestra that maintains ME/CFS cycle. It is not the

concertmaster. In the CDR view, each time someone calls out one particular player
in the orchestra, eg, NK cells, PDH, MTHFR, folate, B12, glutathione, etc., it is
just another part of the integrated response.

I like the orchestra metaphor better than the blind men describing parts of an
elephant because all the parts of the CDR, the “instruments” can actually play a
different tune when directed to do so by the concertmaster. But an elephant’s trunk
is only ever a trunk.

PDH plays one tune in health and another in CFS, but it is still the same enzyme.
If you focus on it alone, you miss the message in the music."
 

Seanko

Well-Known Member
By this, I think Dr Naviaux means it PDH os not the source of the mitochindrial dysfucntion but a symptom of it.

I watched a talk by Oystein Fluge recently & he said that he did not think the Dauer existed. Good to have a differnce of opinion as the race will be on to prove which theories are correct

 

Seanko

Well-Known Member
FLUGE, MELLA, AND ARMSTRONG: MORE SUPPORT FOR DISORDERED METABOLISM IN ME PATIENTS

http://www.meaction.net/2016/12/23/fluge-mella-and-armstrong-more-support-for-disordered-metabolism-in-me-patients/
One of the frequent complaints of patients, researchers, and policymakers about ME research is that the findings are scattered, and the studies, small. One group will discover X is elevated in 20 ME patients, only to find that when the test is done on another 13 patients two years down the line, they don’t show elevated X at all. We’re also confounded by the wide array of research and clinical definitions, from Ramsay to Fukuda, to CCC, to the IOM criteria and beyond: at least 8 frequently-used definitions that describe illnesses that, if not the same, have a great deal of overlapping criteria. Critics have been known to call ME/CFS discoveries “microfindings” because of the tendency of small studies to be debunked later on.
But it may – finally – be time to put the idea to bed that patients “may or may not” have disordered cellular metabolism. The research has been piling up over the past several years and, just in the past two weeks, two studies from two different groups of researchers half a world away have results that support one another.
What this means for patients is nothing less than a potential treatment, and a serious contender for a diagnostic test. But it’s not all good news: the results of at least one of the studies appears to have found far more significant and abundant signs of dysfunction in women than men. Since there is no evidence to support that women with ME/CFS are sicker than men, we are left with the impression of a puzzle with more than a few missing pieces.

Background:

The reason that we can get energy from food is because of a process called cellular respiration. Cellular respiration is traditionally divided up into three processes: glycolysis, the citric acid (or Krebs) cycle, and the electron transport chain. The first of the three, glycolysis, involves the splitting of sugar to produce pyruvate molecules, occurs outside of the mitochondria, and does not require oxygen. The second two processes both occur in the mitochondria, and both need oxygen to work.
The goal of all these processes is to make molecules that have energy-rich chemical bonds, such as ATP and NADH. When a phosphate group breaks off of ATP, the energy that was holding it there is released, and the cell can ‘use’ that energy to do work. This is how we walk, talk, breathe, and even how our cells move fatter molecules into and out of cells.
While glycolysis is often considered the first step in the process, it isn’t truly necessary to get energy for the cell. Fats and proteins feed into the cycle as well, which is why they are considered macronutrients. Fats break down into glycerol and fatty acids, which feed into the citric acid cycle a wee bit further down. And proteins break apart into their constituent amino acids, and feed into the citric acid cycle in several spots.


Yep, this is it.
However, bypassing glycolysis would rob the cell of 2 ATP molecules for every cycle, or about 5% of the energy from the cycle if we consider the ATP molecules’ removal out of context. When we consider that the pyruvate produced during glycolysis is part of what feeds the citric acid cycle, however, the loss of energy-rich molecules might in fact be far higher.
In order to transition from glycolysis to the citric acid cycle, the pyruvate produced from glucose must become Acetyl Co-A. The enzyme complex that catalyzes this process is called the pyruvate dehydrogenase complex, or PDH complex.
If the PDH complex did not function properly, or were blocked, the result would be far less pyruvate turned into Acetyl Co-A, and a dropoff in high-energy molecules down the line.

PDH activity is controlled by multiple different factors, including but not limited to:

  • PDH kinases (PDKs), that inhibit activity of PDH enzymes
  • PDH phosphatases that yank away PDH’s phosphate group so it does not function properly
  • Sirtuin 4 (SIRT4), which is also an inhibitor for PDH
  • PDK1, 2, 3, and 4
A shift in these or their expression means a shift towards higher glucose, lower pyruvate, lower Acetyl Co-A, and fewer energy-rich molecules produced in the cell to do work
Recap:

Cellular respiration!
Goal: make molecules with energy-rich bonds for later use
3 bits:
Glycolysis
Glucose (sugars) –> pyruvate –> acetyl Co-A
Last step requires PDH, which depends on:
PDKs, PDH phosphatases, SIRT4, PDK1—4
Citric Acid Cycle
Electron Transport Chain (ETC)

Armstrong’s Metabolomics:

Christopher Armstrong and colleagues (out of the University of Melbourne) have been working under the theory that amino acid metabolism in ME/CFS patients is disturbed for some time. Their first metabolomics paper, Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients showed overall elevation of blood glucose, implying that glycolysis wasn’t happening as swiftly as in healthy controls. This study also showed signs of acceleration of other cellular processes designed to get energy-rich molecules from other methods, such as accelerated amino acid metabolism.
Then, just a few weeks ago, Armstrong’s team produced a second paper: The association of fecal microbiota and fecal, blood serum and urine metabolites in myalgic encephalomyelitis / chronic fatigue syndrome.
Armstrong’s group found once again that patients had elevated blood glucose levels that were quite significant – 124% the average of healthy controls, with a p value of 0.002. Armstrong also found blood levels of many amino acids were decreased, including glutamate, hypoxanthine, lactate, phenylalanine, and acetate.
All of Armstrong’s findings taken together strongly imply impaired glycolysis in ME/CFS patients, and a corresponding decrease in citric acid cycle activity, along with some upregulated amino acid metabolism seemingly to make up for the lack.
Armstrong had some fascinating conclusions regarding the gut environment of ME/CFS patients as well. Stay tuned for more on those findings later! However, Armstrong’s and Fluge and Mella’s findings regarding amino acid metabolism relate very closely, so let’s move on for now to their findings.

Fluge and Mella’s PDH Hypothesis:

Fluge and Mella’s hypothesis was that perhaps PDH function (and AMPK function) is impaired in ME/CFS patients. Just like Armstrong, they only included patients who met the Canadian Consensus Criteria. Their study was large, with 200 patients and over 100 healthy controls. Interestingly, they divvied their patients into male and female groups, and the results were – at least to this reader – very surprising.
First, the researchers divided the amino acids into three groups:

  • Category 1, which are converted to pyruvate, and depend on PDH to be oxidized
  • Category 2, which enter oxidation pathway as Acetyl Co-A
  • Category 3, which are converted to citric acid cycle intermediates
Then they measured each of the levels of these amino acids in the blood.
Here is what they found:

Note that the red arrow trends depicted refer to what was found in female patients only.
You can see that the trend to dysfunction is clear from Category 2 and onward. This strongly implies that there is not a real issue with amino acids that turn into pyruvate, but a significant ‘drain’ on amino acids thereafter. This implies that the ‘issue’ is after glucose becomes pyruvate, but before pyruvate becomes Acetyl Co-A… in other words, it could well be an issue with the enzyme complex we mentioned before, since that catalyzes pyruvate into Acetyl Co-A.
Keep in mind depleted amino acids mean we’re using them up, not that we can’t make them. Amino acids here are serving as an alternate source of fuel for our cells, and that is why they are found in far lower levels in the blood than they are in healthy controls.
But amino acids have other jobs to do besides energy-molecule generation. Could their absence be the reason behind some of the symptoms that many women with ME/CFS experience?
Fluge and Mella next set out to discover just that.

Endothelial dysfunction and ME/CFS

Endothelial dysfunction is a source of concern for ME/CFS patients and may be the root of some of its symptoms. Previous studies have found evidence of disordered endothelial dysfunction in ME (Newton et al, 2012 – no, not that Newton).
Therefore, Fluge and Mella set out to see whether amino acids necessary for proper endothelial function were reduced in the blood, including arginine, asymmetric dimethylarginine, homoarginine, 1-methylhistidine, 3-methylhistidine, and symmetric dimethylarginine.
The result? Symmetric dimethylarginine was significantly reduced, as was 3-methylhistidine – the first, only in women, and the second, only in men.

Other amino acid associations

Importantly, no correlation was made between amino acids and physical activity levels. Unlike in some studies, ‘activity’ was measured objectively using a 24-hour measure of steps taken in the ME/CFS group. There was an association between cysteine levels and activity, but not in depletion of amino acids in general.
There was some correlation between some amino acid levels and body mass index (BMI), but no matter what, amino acid levels in ME/CFS patients were lower than they were for healthy controls of the same or similar BMI.
In women, a significant association was found between disease severity and phenylalanine; the longer the woman had been ill, the higher her levels of this amino acid.
Notably, the lower her category 1 amino acids, the lower a female patient’s quality of life.
PDH gene expression
So, after supposing that PDH is the step that is likely the one that’s ‘off’, Fluge and Mella and their team tested mRNA expression of all the inhibitory molecules we discussed earlier and found that their expression was elevated. Remember: increasing an inhibitor has a negative effect on PDH, which means fewer glycolysis products becoming Acetyl Co-A, and less energy!
Inhibitory kinases PDK1, 2, and 4 all had elevated mRNA expression, as did SIRT4. PPAR-gamma was increased in the peripheral mononuclear cells of patients as well.
And finally we have a result for the gentlemen! These findings were consistent across gender lines.
Moreover, PDK1 expression correlated well to severity of illness: the higher the expression of this inhibitor, the worse symptoms appeared to be.
The same association was not found for the other inhibitory molecules, but that sounds like a potential blood test to me… provided these findings can be replicated consistently in future studies.

Can ordinary cells become ‘infected’ with ME/CFS’s metabolic madness?

Here comes my favorite part: studying the effect of bathing normal skeletal muscle cells in ME/CFS blood.
Before we get there, however, it’s worth mentioning that Fluge and Mella would not be the first to study AMPK function in ME/CFS patients: Brown and colleagues, including Julie Newton, studied AMPK function in muscle cells in 2015.

The research team gathered serum from 12 patients who they classified as either severe or very severe sufferers.
They found that basal (resting) amino acid-driven respiration was moderately elevated in ME/CFS patients’ cells. This echoes similar findings from just a few months ago, when a paper reported that ME/CFS patients’ cells were just raring to go. In that study, the researchers noted that when they put their ME cells in an amino-acid-rich medium, they began producing copious energy-rich molecules, predominantly from mitochondrial processes rather than glycolytic ones. This makes sense, since they were taken out the famine and desolation of an ME patient and placed in a bath rich with delicious nutrients. Their findings appear to agree with Fluge and Mella’s.

The serum of ME/CFS patients, when cultured with ordinary skeletal muscle cells, increased the rate of mitochondrial metabolism and respiration, especially when the scientists created chemical conditions that mimicked ‘energetic strain’.
What does this all mean?
To start with, it means that ME/CFS patients are getting very little energy from sugar or carbohydrates – and there are other, good reasons to ease back from them (more on that regarding C. Armstrong’s paper, later!) Female patients especially should turn to amino-acid-rich foods and supplements.
What about our male patients, however? Could it be that if we examined their fatty acid oxidation byproducts, we’d find a similar sort of depletion we see in the amino acids of women? Only time and further experimentation will tell.
The skeletal muscle test shows us that the factors that inhibit energy metabolism are in fact blood-borne, but this does not (necessarily) mean that the disease itself is communicable by blood transfusion. It may well be that after a short period of time, a healthy person’s cells would shift back to obtaining more of their energy from glycolysis, returning to normal.
Fluge and Mella found support for the idea that PDH dysregulation / inhibition is a key factor in pathogenesis. It’s too soon to be certain, but not too soon to be hopeful: it’s possible that these findings could lead to a single-measure blood test for ME/CFS patients. What a fabulous holiday present that would be!
“Give me a lever and a place to stand and I will move the earth.” Could PDH be the ‘lever’ ME/CFS patients have been waiting for? If we can find a treatment that will ‘move’ this one target, it could make a huge difference in the quality of life of patients.
What does this have to do with pathogens? It could have quite a lot to do with them! As C. Armstrong’s paper notes, “the… microbiota has the ability to modulate host metabolism.” This may well tie in with Naviaux’s work as well! More on that down the line, folks… stay tuned.


Note that this is an opinion piece! Do not make treatment decisions based off of the word of bloggers alone.
 

Strike me lucky

Well-Known Member
Only had a quick glance but it appears to show theres a catabolic process going on where protein is being broken down into amino acids for fuel. Almost like a muscle wasting disease. Catabolism is also very closely related to oxidative stress.

I can see a similar issue with hiv which would be a more severe and rapid muscle wasting disease. Also backs up research with anabolic steroids such as nandrolone or oxandrolone (very safe when monitored by drs) used to stop muscle wasting and rebuild lost muscle tissue. What initially suprised researchers was that improving the patients anabolic state had a significant impact on the patients immune function and greatly increased their quality of life.

Several drs in the late 1980s early 90s mentioned cfsme patients being in a catabolic state. This seems to have been ignored, partly because of the stigma of anabolic steroid use. I cant recall which drs but remember them using nandrolone as a part of their treatment protocol along with treating infections and improving immune function etc.

If we ignore the whole bodybuilding mentality of steroid use and look at its use for medicine, it is a treatment for anemia which increase red blood cells, improves energy production by improving glycogen and creatine storage as well as insulin sensitivity , it improves nitrogen retention and protein turn over ie replacing cells in the body more quickly and efficiently . The sum of all this increase general recovery processes that would reduce pem. The main reason why athletes use these medications is to greatly improve recovery so they can train more often.

Whats causing this catabolic process? An immune system in overdrive be it from some autoimmune process or some type of chronic infection.

I think cfsme can learn alot by how hiv drs treat catabolic issue in hiv and use them in cfsme for similar reasons.

Signficant protein intake can help along with anticatabolic supplements such as branch chained amino acids, glutamine and hmb which is related to isoluciene and luciene which i noticed in the recent research. Correct balance of hormones is very important in fending of catabolism. The 2 anabolic steroids nandrolone and oxandrolone which are very safe could make a great impact but health regulators are scared to approve the substances for more uses. It took a big push from the hiv community to get them prescribed in hiv where it saved alot of lives.

More research is needed in treating treating catabolism in cfsme.
 
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Remy

Administrator
So any ideas why something like this triheptanoin hasn't been tried or looked at in ME/CFS? It seems fairly readily available, at least as a research chemical. It's a triglyceride.

This all relates to Huntington's disease...but sounds pretty familiar to what Fluge and Mella have found too, right?

There is strong evidence for hypometabolism in the brain of patients with HD.

For example, glucose consumption is reduced, especially in the basal ganglia, even in presymptomatic mutation carriers.2,4

Studies in animal models have revealed decreased adenosine triphosphate (ATP) concentrations in the brain of HD mouse models.5

There are also nonneurologic symptoms at the early stage of the disease, such as weight loss despite enhanced caloric intake, which suggest a hypercatabolism in HD.6

Reduced concentrations of branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—have been found in plasma samples of patients with HD as early as in presymptomatic carriers even when they were on a high-caloric diet.6

We hypothesized that decreased circulating levels of BCAAs reflect their mitochondrial oxidation in order to provide 2 key intermediates for the Krebs cycle: acetyl coenzyme A (acetyl-CoA) and succinyl-CoA.6 Consequently, therapies aiming at providing substrates to the Krebs cycle may be of special interest in HD.

We previously showed that dietary anaplerotic therapy—replenishing the pool of metabolic intermediates in the Krebs cycle—was able to improve peripheral energy metabolism in HD using 31P magnetic resonance spectroscopy (MRS) in muscle.7
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336068/
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
So any ideas why something like this triheptanoin hasn't been tried or looked at in ME/CFS? It seems fairly readily available, at least as a research chemical. It's a triglyceride.

This all relates to Huntington's disease...but sounds pretty familiar to what Fluge and Mella have found too, right?



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336068/
How interesting - particularly the reduced metabolism in the basal ganglia.

This seems so similar - great find. I am going to pass onto Chris Armstrong :)


Reduced concentrations of branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—have been found in plasma samples of patients with HD as early as in presymptomatic carriers even when they were on a high-caloric diet.6

We hypothesized that decreased circulating levels of BCAAs reflect their mitochondrial oxidation in order to provide 2 key intermediates for the Krebs cycle: acetyl coenzyme A (acetyl-CoA) and succinyl-CoA.6Consequently, therapies aiming at providing substrates to the Krebs cycle may be of special interest in HD.
 

Remy

Administrator
I'm trying to get all this straight and I keep getting hung up on the role of biotin...

From what I can tell, pyruvate has two options once it crosses into the mitochondria. It can either become oxaloacetate (through pyruvate carboxylase) or it can become acetyl coA (through pyruvate dehydrogenase).

[bimg=no-lightbox]http://usmle-review.org/gluconeogenesis.gif[/bimg]

So if in ME/CFS, there is a deficiency in pyruvate dehydrogenase, it seems to be reasonable that more of the pyruvate is heading down the alternate pathway where it can contribute to gluconeogenesis. This pathway would also lead to the depletion of amino acids that was seen.

So if that is true, that pathway is dependent on biotin as a cofactor...so wouldn't decreasing biotin levels also inhibit that pathway? And if that pathway is inhibited, is it conceivable that might force more of the pyruvate down the PDH pathway to acetyl coA? Or would it just stuff up the only somewhat functional pathway and make things worse?

There are studies that use avidin (egg white protein) to bind biotin and it works to prevent gluconeogenesis so well that it's been identified as a potential diabetes target.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238542/pdf/nihms-200881.pdf

Also alpha lipoid acid seems to reduce biotin dependent carboxylases and would seem to have a similar effect perhaps of slowing down that pathway. Alpha lipoid acid has also been implicated as a treatment for diabetes, possibly by inhibiting gluconeogenesis, and many people find it helpful in ME/CFS too.

http://m.jn.nutrition.org/content/127/9/1776.full

So should we all start drinking raw egg whites (can't be cooked!) to bind up biotin?
 

Seanko

Well-Known Member
@Cort Reduced levels of BCAAs have been found in the Naviaux and Fluge & Mella studies too.

After reading the Naviaux paper, i took a punt on trying BCAAs. Difficult to be objective but I would say in association with Creatine, they have helped.
 
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