'Adding Pyruvate makes ME cells normal' - What questions does this prompt?

[adreno]

More about HIF-1:

The oxygen tension-dependent transcriptional factor, hypoxia inducible factor-1 (HIF-1), is responsible for the induction of genes that facilitate the adaption and survival of cells exposed to hypoxia [2]. HIF-1 activation induces a diverse range of target genes, encompassing a wide variety of cellular processes, including angiogenesis, erythropoiesis, energy metabolism, cell proliferation, and cell cycle control [3]. HIF-1 can improve the redox environment [4], increase blood oxygen and glucose supply, and affect iron metabolism by regulating its target genes.

It looks like HIF-1 signaling is impaired in neurodegenerative diseases, making it a potential treatment target:

The brain consumes a large quantity of oxygen and demonstrates a high vulnerability at conditions with impaired oxygen supply. It has been suggested that reduced oxygen supply plays a key role in neurodegeneration during the aging process [5]. Pathological processes such as oxidative stress, impaired oxygen or glucose supply, and disruption of iron homeostasis are common in neurodegenerative diseases [6–8]. This raises the possibility that HIF-1 is a potential therapeutic target for these neurodegenerative diseases. In this review, we focus on the mechanisms of HIF-1 regulation and roles of HIF-1 in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s diseases (HD). We also summarized recent drug development based on HIF-1 pathway in neurodegenerative diseases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213300/

 

[AdamS]

Just found this...from 2000, but can be related to the findings of Fluge & Mella about PDH:

Acta Physiol Scand. 2000 Apr;168(4):457-64.
Muscle oxygen uptake in humans at onset of and during intense exercise.
Bangsbo J1.
Author information

Abstract
This review presents data on human muscle oxygen consumption in the initial phase of exercise as well as on muscle maximal oxygen uptake. It also discusses mechanistic limiting factors related to oxygen utilization at the onset of exercise and of maximal aerobic power of skeletal muscle. Direct measurements of oxygen utilization of a well-defined muscle show that contracting muscles utilize oxygen within a few seconds of exercise onset and that it takes some 45 s before oxygen extraction is maximal. The delayed oxygen utilization in the initial phase of intense exercise does not appear to be caused by insufficient oxygen availability. But it may rather be the result of a non-optimal distribution of blood flow in the exercising muscles and a limitation in the rate of oxygen extraction by the contracting muscle cells. The latter limitation does not appear to be caused by an insufficient activation of the enzyme pyruvate dehydrogenase. The maximal oxygen uptake of skeletal muscle is around 300-400 mL min-1 kg-1. This uptake rate corresponds to a TCA cycle rate of 4-5 mmol min-1 kg-1, which is of the same magnitude as the activity of oxyglutarate dehydrogenase and pyruvate dehydrogenase, suggesting that these enzymes may be rate limiting for oxygen uptake when an isolated muscle is exercising.

 

[msf]

Bacterial Lipopolysaccharides (LPS), like from a leaky gut, can cause an increase in HIF1, a decrease in oxygen consumption, an increase in PDK1 and therefore an inhibition of PDH.

LINK

Looks like we have had a similar reading list lately. Damn, I should have published in sections! Haha. I still feel I should put together what I have read recently into one blog/OP, unless of course you beat me to it!

 

[ljimbo423]

Looks like we have had a similar reading list lately. Damn, I should have published in sections! Haha. I still feel I should put together what I have read recently into one blog/OP, unless of course you beat me to it!

Seems like we both might be on the same page! I have not done a blog and would be very interested in one you might write. I think this is very good, important info. and I feel like the more people that have access to it the better!

 

[kangaSue]

It would be more relevant to ask why we are hypoxic in the first place.

Simple answer is inflammation. Inflammation causes hypoxia, hypoxia causes inflammation. If you've got gut issues, then you likely have inflammation causing hypoxia but incidently, inflammation is not necessarily overt enough to show up as an ESR or C-Reactive Protein issue.
http://www.pnas.org/content/110/46/18351.full.pdf

 

[nandixon]

If Pyruvate fixes ME patient's cells, does this suggest that it isn’t being made properly or that it is being made but not transported/utilised effectively?

I've posted elsewhere about this before. I'm pretty certain that the normalization with pyruvate in Ron Davis’ test device is excellent confirmation that the pyruvate dehydrogenase (PDH) complex is in fact being inhibited by the PDH kinases (PDK1, 2 & 4) as found by Fluge & Mella.

Pyruvate is a potent inhibitor of the PDKs. Under the relatively simple test conditions Ron Davis is using I think it's most likely that the added pyruvate is simply de-inhibiting the PDH complex - by inhibiting the PDKs.

This is because of the following:

1.The activity of the PDH complex is under the complete control of the PDKs and the PDH phosphatases (PDPs). The reaction that the PDH complex performs in converting pyruvate to acetyl-CoA cannot be “driven” by adding additional pyruvate like you'd be able to do with many other enzymatic reactions.

2.No other pathways utilizing pyruvate as an energy source come even close to the amount of ATP produced by injection of the acetyl-CoA made by the PDH complex into the Krebs Cycle.

So the question is, what is causing the increased levels of PDKs? The unknown substance in the blood would presumably somehow be causing this.

 

[nandixon]

I found this today, an older study, but seemed relevant to the work that Naviaux and Davis are doing. Naviaux found that in males, over 50% (16/30) of the sphingolipids that were decreased were ceramides, and 47% (14/30) were sphingomyelin species. In females, 86% (18/21) were ceramides.

The de novo synthesis of sphingolipids including ceramides requires acetyl coenzyme A. The major generator of acetyl-CoA is the pyruvate dehydrogenase (PDH) complex. With that complex being inhibited, that may be the simplest explanation for why Naviaux found the low levels of sphingolipids.

 

[AdamS]

@nandixon Thanks a lot for your input, it's really helpful. I can't wait to see what the researchers find next, seems like we're getting close to a breakthrough.

 

[AdamS]

Also @nandixon out of interest, do you know anything about dichloroacetate (DCA)?

I was reading this and came across it, I didn't know if it would be relevant to ME patients though. I realise that it wouldn't actually be solving the root cause but wondered if it (or in fact any PDK inhibitor) could help symptoms at all. My guess is that it's not so simple though.

From link above:

Recent studies revealed that targeting PDHK by dichloroacetate (DCA) shifts cancer cell metabolism from glycolysis to oxidative phosphorylation and inhibits tumor growth (Bonnet et al., 2007). This finding suggests that the PDHK/PDH axis may contribute to cancer cell metabolism and tumor growth.

 

[nandixon]

Also @nandixon out of interest, do you know anything about dichloroacetate (DCA)?

Dichloroacetate is certainly a theoretical possibility for inhibiting the PDKs in order to de-inhibit the PDH complex. But you'd need to take large quantities because it's not a very specific/efficient drug. And the older you are, i.e., older than a child, the more likely you are to develop the peripheral neuropathy problem it's infamous for. The neuropathy is usually reversible when the DCA is stopped but it's pretty well guaranteed to happen with the large doses of DCA that would be needed to make a difference in ME/CFS, I'm afraid.

 

[Jesse2233]

Dichloroacetate is certainly a theoretical possibility for inhibiting the PDKs in order to de-inhibit the PDH complex. But you'd need to take large quantities because it's not a very specific/efficient drug. And the older you are, i.e., older than a child, the more likely you are to develop the peripheral neuropathy problem it's infamous for. The neuropathy is usually reversible when the DCA is stopped but it's pretty well guaranteed to happen with the large doses of DCA that would be needed to make a difference in ME/CFS, I'm afraid.

Do you think pulsing the Dichloroacetate in high doses would do any good?

I'm meeting with a mitochondrial geneticist next month, and this is one of the drugs on my list to ask him about

 

[nandixon]

Do you think pulsing the Dichloroacetate in high doses would do any good?

I'm not sure. It looks like that's been tried in cancer with some success with both increased effectiveness and reduced toxicity, I think, but it requires administration by IV rather than orally.

 

[TreePerson]

I've posted elsewhere about this before. I'm pretty certain that the normalization with pyruvate in Ron Davis’ test device is excellent confirmation that the pyruvate dehydrogenase (PDH) complex is in fact being inhibited by the PDH kinases (PDK1, 2 & 4) as found by Fluge & Mella.

Pyruvate is a potent inhibitor of the PDKs. Under the relatively simple test conditions Ron Davis is using I think it's most likely that the added pyruvate is simply de-inhibiting the PDH complex - by inhibiting the PDKs.

This is because of the following:

1.The activity of the PDH complex is under the complete control of the PDKs and the PDH phosphatases (PDPs). The reaction that the PDH complex performs in converting pyruvate to acetyl-CoA cannot be “driven” by adding additional pyruvate like you'd be able to do with many other enzymatic reactions.

2.No other pathways utilizing pyruvate as an energy source come even close to the amount of ATP produced by injection of the acetyl-CoA made by the PDH complex into the Krebs Cycle.

So the question is, what is causing the increased levels of PDKs? The unknown substance in the blood would presumably somehow be causing this.

I apologise in advance if this is a really naive or stupid question and for taking up your time but you seem to be particularly knowledgeable. A Couple of times recently I have had an involuntary adrenaline burst due being in a very difficult or stressful situation. Both times I have noticed a really marked temporary increase in energy/capacity. Usually I feel considerably worse afterwards. Is there anything about adrenaline and or the receptors that could play a part in this pyruvate puzzle? Blocking or unblocking PDH and PDH kinase as you describe? Or is it simply that adrenaline massively opens up all energy pathways?

 

[overtheedge]

I've been thinking about trying some pyruvate out since mitochondrial supplements have done really well by me.

Has anyone here supplemented pyruvate or know others who have?

 

[AdamS]

@overtheedge From what I understand, if PDK1 is raised then pyruvate is shunted away from the TCA cycle so supplementing it might not help. The issue seems to be with pyruvate utilisation not availability.

 

[Jesse2233]

i wonder what effect supplementing acetyl co-A (if there were such a supplement) would have

 

[pattismith]

It suggests the presence of mercury and/or arsenic inhibiting this pathway:

https://www.ncbi.nlm.nih.gov/books/NBK22340/

"Symptoms similar to those of beriberi arise if an organism is exposed to mercury or arsenite (AsO33-). Both elements have a high affinity for neighboring sulfhydryls, such as those in the reduced dihydrolipoyl groups of the dihydrolipoyl dehydrogenase component of the pyruvate dehydrogenase complex (Figure 17.20). The binding of mercury or arsenite to the dihydrolipoyl groups inhibits the complex and leads to central nervous system pathologies."

interestingly, Arsenic has a link to schizophrenia and is also an endocrine disruptor

 

[bertiedog]

My recent Organic Acid test could not detect ANY pyruvate. The test was on the first morning void so basically after any overnight fast.

No wonder I feel half dead till I have eaten some carbs on waking along with my steroid and thyroid meds.

Pam

 

[pattismith]

I found this really good picture about how PDH is inhibited by PDK4 activation.
I wonder if PDK4 is activated in ME, do we know?

Transcriptional regulation pathways of PDK4 in different tissues under various nutritional states.

Inactivation of PDC by up-regulation of PDK4 can switch glucose catabolism to fatty acid utilization.

There are different transcriptional regulation pathways in skeletal muscle, liver, white adipose tissue and heart under various nutritional conditions (energy deprivation, high fat diet consumption, exercise, diseases, drugs). Akt/PKB: protein kinase B; AMPK: 5’-AMP-activated protein kinase; CD36: Cluster of differentiation 36; C/EBPβ: CCAAT/enhancer-binding protein β; eIF4E: Eukaryotic initiation factor 4E; ERRα: Estrogen related receptor α; FAT: Fatty acid transporter; FoxO1: Forkhead box protein O1; LXR: Liver X receptor; MAPK: p38 mitogen-activated protein kinase; PDC: Pyruvate dehydrogenase complex; PDK4: Pyruvate dehydrogenase kinase 4; PGC1α: PPARγ co-activator 1α; PPARs: Peroxisome proliferator-activated receptors; SHP: Small heterodimer partner; STAT5: Signal transducer and activator of transcription 5.

 

[caledonia]

"Symptoms similar to those of beriberi arise if an organism is exposed to mercury or arsenite (AsO33-). Both elements have a high affinity for neighboring sulfhydryls, such as those in the reduced dihydrolipoyl groups of the dihydrolipoyl dehydrogenase component of the pyruvate dehydrogenase complex (Figure 17.20). The binding of mercury or arsenite to the dihydrolipoyl groups inhibits the complex and leads to central nervous system pathologies."

interestingly, Arsenic has a link to schizophrenia and is also an endocrine disruptor

It's also a known carcinogen.

If you've eaten any chicken in the US between 1949 and 2016, you have arsenic. Yes, it was added to chicken feed for decades...