Suggested Pathology of Systemic Exertion Intolerance Disease: Impairment of E2/E3 Subunit of PDH

[SlamDancin]

@msf That’s interesting thanks for the anecdote. Personally, I have spine problems (scoliosis with reduced lung capacity, a few other things but never diagnosed CCI) and I can attest that a simple measure of how much lactic acid burning I get from walking up stairs is a pretty good indicator of my overall health status. Therefore I don’t doubt at all that PDH is involved in the whole picture. I have tried a few different ways to activate PDH and still take Calcium, Thiamine, Biotin and Ethyl Pyruvate/Ethyl Acetoacetate. I feel like these things have helped but unless I maintain my physical therapy regimen these things lose efficacy. I really do believe that there may be a fundamental structural problem we have or had that causes permanent PDH suppression. Like I said, stroke causes this and the secondary damage is caused by PDH suppression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126256/

“Here, we evaluate proposed mechanisms of PDH-mediated neurodysfunction in stroke, including oxidative stress, altered regulatory enzymatic control, and loss of PDH activity....

We also describe the neuroprotective influence of antioxidants, dichloroacetate, acetyl-L-carnitine, and combined therapy with ethanol and normobaric oxygen, explained in relation to PDH modulation.”

 

[msf]

@msf That’s interesting thanks for the anecdote. Personally, I have spine problems (scoliosis with reduced lung capacity, a few other things but never diagnosed CCI) and I can attest that a simple measure of how much lactic acid burning I get from walking up stairs is a pretty good indicator of my overall health status. Therefore I don’t doubt at all that PDH is involved in the whole picture. I have tried a few different ways to activate PDH and still take Calcium, Thiamine, Biotin and Ethyl Pyruvate/Ethyl Acetoacetate. I feel like these things have helped but unless I maintain my physical therapy regimen these things lose efficacy. I really do believe that there may be a fundamental structural problem we have or had that causes permanent PDH suppression. Like I said, stroke causes this and the secondary damage is caused by PDH suppression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126256/

“Here, we evaluate proposed mechanisms of PDH-mediated neurodysfunction in stroke, including oxidative stress, altered regulatory enzymatic control, and loss of PDH activity.”

Sounds like you have researched your own condition a lot, so I am sure you know a lot about it, but I am still to be convinced that the majority of people with ME have causative structural problems. My own neck problems (semi permanent crick in the neck) only presented themselves after I got ME, probably because of the lack of physical exercise.

 

[SlamDancin]

@msf For sure, I think it’s heterogeneous in causation but PDH is probably involved no matter what the base cause. I just added another section from the paper I quoted above where they discuss DCA and some other methods to attack PDH suppression that you may be interested in.

 

[gregh286]

Perhaps someone who understands the chemistry better than me could suggest whether taking oxalate should be more or less effective than taking things that affect PDC directly (such as ALA and DCA), or things that affect AMPK (like reservatrol). These supplements have had a dramatic effect on me (with peripheral neuropathy side effects in the case of DCA), so the idea of a supplement that might be more effective than these is very exciting!

Same here. I have a energy partnership with dca ....ala with a high confidence interval.
Might get the spinach out.
Hope then thread stays alive and has some good minds mull over it.

 

[SlamDancin]

Same here. I have a energy partnership with dca ....ala with a high confidence interval.
Might get the spinach out.
Hope then thread stays alive and has some good minds mull over it.

Salute comrade. Good minds are onto this it’s only a matter of time. We’ve got this.

 

[JES]

@sb4 @JES @ScottTriGuy @junkcrap50

Good research y’all. Since it’s been said even by the patent holders that other high oxalate foods don’t seem to work the same as Spinach, I wanted to bring back up Rubiscolins (I misspelled these in my previous post), which are unique opioid peptides apparently unique to Spinach (and other green leafy vegetables).

https://mybiohack.com/blog/rubiscolins-rubisco-spinach-opioid

This article gives some possible hints at why Spinach may help ME/CFS with mechanisms outside of their oxalate content.

Interesting. I remember @mariovitali pointing out that spinach contains something called dolichol, which apparently could help patients with a certain metabolic disease. So there are certainly several possibilities here.

One thing I forgot to mention was that I also briefly tried to take my spinach dose together with calcium or magnesium (I think it was calcium carbonate). I did this in hopes to reduce the kidney pain I got when eating large amounts of spinach on an empty stomach. Over the next couple of days I noticed there was no longer any "initial" positive effect or at least the effect was much reduced compared to just ingesting spinach on its own.

Again this correlates to what was observed in the Bohne patent, i.e. when they gave patients a "quenched drinkable" with some form of carbonate in it, the patients noticed it had lost its positive effect. I will probably retest this again sometimes this summer, but based on my experience it seems that oxalates are at least in some form a necessary part of this effect.

(Apologizes if this thread got derailed into spinach completely.)

 

[SlamDancin]

Guys I promised I’d come back with references about Somatostatin (something Dr Theorides is studying as part of the NIH exercise series of studies). I know this thread has been all over the place but I figured it’d be easier to follow here than in a new thread.

“CSF-contacting neurons are present in all vertebrates and are located mainly in the hypothalamic area and the spinal cord. Here, we report that the somatostatin-/GABA-expressing CSF-c neurons in the lamprey hypothalamus sense bidirectional deviations in the extracellular pH and do so via different molecular mechanisms. They also serve as mechanoreceptors. The hypothalamic CSF-c neurons have extensive axonal ramifications and may decrease the level of motor activity via release of somatostatin. In conclusion, hypothalamic somatostatin-/GABA-expressing CSF-c neurons, as well as their spinal counterpart, represent a novel homeostatic mechanism designed to sense any deviation from physiological pH and thus constitute a feedback regulatory system intrinsic to the CNS, possibly serving a protective role from damage caused by changes in pH.”

“In the same neuron, acidic and alkaline responses are mediated through ASIC3-like and PKD2L1 channels, respectively.”

https://www.ncbi.nlm.nih.gov/m/pubmed/30037834/?i=1&from=asic3 somatostatin


“During ongoing locomotor activity in the isolated spinal cord, both an increase and as a decrease of pH will reduce the locomotor burst rate. A somatostatin antagonist blocks these effects, suggesting that CSF-c neurons are responsible for the suppression of locomotor activity. CSF-c neurons thus represent a novel innate homeostatic mechanism, designed to sense any deviation from physiological pH and to respond by causing a depression of the motor activity. Because CSF-c neurons are found in all vertebrates, their pH-sensing function is most likely conserved.”

https://www.ncbi.nlm.nih.gov/m/pubmed/27133867/?i=2&from=asic3 somatostatin

A very quick cursory search seems to indicate that somatostatin has some relationship to PDH flux in relation to the TCA, however from the abstract alone it’s hard to decipher. Also this is in the liver not the CNS;

“In this study we examined the individual effects of insulin and substrate availability on the regulation of pyruvate dehydrogenase flux (V(PDH) ) to tricarboxylic acid flux (V(TCA) ) in livers of awake rats with lipid-induced hepatic insulin resistance. V(PDH) /V(TCA) flux was estimated from the [4-(13) C]glutamate/[3-(13) C]alanine enrichments in liver extracts and assessed under conditions of fasting and during a hyperinsulinemic-euglycemic clamp, whereas the effects of increased plasma glucose concentration on V(PDH) /V(TCA) flux was assessed during a hyperglycemic clamp in conjunction with infusions of somatostatin and insulin to maintain basal concentrations of insulin.”

Full paper;

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077048/

 

[PhoenixDown]

I always assumed it was just another name for CFS.

No, the whole point was too distance ME patients from all the bad things associated with CFS such as fraudulent research and the biopsychosocial viewpoint. For example ME is not just feeling a little tired.

 

[SlamDancin]

Can any of you guys help me parse this paper?

@sb4 @mariovitali @msf @JES @junkcrap50

Somatostatin Inhibits Oxidative Respiration in Pancreatic β-Cells


Somatostatin potently inhibits insulin secretion from pancreatic β-cells. It does so via activation of ATP-sensitive K+-channels (KATP) and G protein-regulated inwardly rectifying K+-channels, which act to decrease voltage-gated Ca2+-influx, a process central to exocytosis. Because KATP channels, and indeed insulin secretion, is controlled by glucose oxidation, we investigated whether somatostatin inhibits insulin secretion by direct effects on glucose metabolism. Oxidative metabolism in β-cells was monitored by measuring changes in the O2 consumption (ΔO2) of isolated mouse islets and MIN6 cells, a murine-derived β-cell line. In both models, glucose-stimulated ΔO2, an effect closely associated with inhibition of KATPchannel activity and induction of electrical activity (r > 0.98). At 100 nM, somatostatin abolished glucose-stimulated ΔO2 in mouse islets (n = 5, P < 0.05) and inhibited it by 80 ± 28% (n = 17, P < 0.01) in MIN6 cells. Removal of extracellular Ca2+, 5 mMCo2+, or 20 μM nifedipine, conditions that inhibit voltage-gated Ca2+ influx, did not mimic but either blocked or reduced the effect of the peptide on ΔO2. The nutrient secretagogues, methylpyruvate (10 mM) and α-ketoisocaproate (20 mM), also stimulated ΔO2, but this was unaffected by somatostatin. Somatostatin also reversed glucose-induced hyperpolarization of the mitochondrial membrane potential monitored using rhodamine-123. Application of somatostatin receptor selective agonists demonstrated that the peptide worked through activation of the type 5 somatostatin receptor. In conclusion, somatostatin inhibits glucose metabolism in murine β-cells by an unidentified Ca2+-dependent mechanism. This represents a new signaling pathway by which somatostatin can inhibit cellular functions regulated by glucose metabolism

https://academic.oup.com/endo/article/147/3/1527/2501456

This reminds me of the recent glucose metabolism problems detailed by Professor Neil McGregor and outlined in @Cort ’s latest write up

 

[Wishful]

I think we have discussed this before, but I am struggling to understand what stops you doing more than a few minutes of certain types of exercise if it isn't lactic acid - I wasn't aware that biology had other ways to stop humans over exerting themselves,

I'm not sure what is involved with the 'stop doing that' message when I do certain activities, such as washing windows. I'm not sure why some muscle groups would have such a large and immediate increase in lactic acid while other muscle groups don't. Actually, it occurs even in the same muscle groups, just with a different range of extension (or contraction?). For example, walking for hours didn't cause problems, but climbing a ladder (same muscle groups strained differently) did.

For whatever it's worth, I've been doing lots of ladder climbing over the last week (re-roofing, 30' up). Sore muscles in the morning, but no PEM, since I've been taking my cumin on schedule. Tylenol does help with the muscle soreness. I finished half of the hardest part today, and I'm not too upset that the weather will be giving me at least a few day's rest.

 

[sb4]

@JES I wonder if it would be worth trying your spinach experiment again but taking potassium citrate with it. As I linked earlier in the thread, it seems that potassium citrate can reduce calcium oxalate formation by increasing the pH of urine and binding calcium.

As far as I understand, the transported that moves citrate into the urine, activates the transporter that moves oxalate into the urine. One in the urine, the citrate binds the calcium to prevent calcium oxalate stones. This can only occur if the kidneys are high pH. If they are low pH, the citrate moves the other way and is scavanged from the urine and instead acid loads are dumped there. This leaves less citrate to bind calcium and possibly more oxalate in the kidneys.

I also found this which has a bunch of studies showing reduced stone formation with K citrate.

@SlamDancin Yeah what you are saying makes sense. Why does only spinach seem to work if it is just the oxalates? I suppose the researches would say it is something to do with the ratio of soluble to insoluble or a specific bell shape dose that works. I will read the stuff you posted.

I will say my gut feeling is that insulin signalling probably isn't whats going wrong, it may be a secondary effect. I think the glucose can get into cells ok, but the problem is using it.

 

[sb4]

I really do believe that there may be a fundamental structural problem we have or had that causes permanent PDH suppression. Like I said, stroke causes this and the secondary damage is caused by PDH suppression.

I think this is really interesting as it could link CCI with CFS. Do you have more info on it?

 

[ScottTriGuy]

@msf ... I feel like these things have helped but unless I maintain my physical therapy regimen these things lose efficacy. I really do believe that there may be a fundamental structural problem we have or had that causes permanent PDH suppression. Like I said, stroke causes this and the secondary damage is caused by PDH suppression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126256/

“Here, we evaluate proposed mechanisms of PDH-mediated neurodysfunction in stroke, including oxidative stress, altered regulatory enzymatic control, and loss of PDH activity....

We also describe the neuroprotective influence of antioxidants, dichloroacetate, acetyl-L-carnitine, and combined therapy with ethanol and normobaric oxygen, explained in relation to PDH modulation.”

I think this is really interesting as it could link CCI with CFS. Do you have more info on it?

And tagging @jeff_w in case he's aware of any research.

 

[SlamDancin]

@sb4 @ScottTriGuy @jeff_w

I found the paper that I remember reading. I was slightly misremembering, it wasn’t stroke but Subarachnoid Hemorrhage (SAH);

“The results of this study demonstrate for the first time a reduction of PDH activity following SAH, independent of supply of substrates and may be an independent factor contributing to a derangement of oxidative metabolism, failure of oxygen utilization, and secondary brain damage.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306203/

I just woke up so you guys feel free to look into this full paper. I haven’t gone through the whole thing yet

 

[SlamDancin]

By the way, although it hasn’t been definitively diagnosed yet, I participated in the latest U of Utah Lights study on ATP gene study and I have results indicitating Occipital Horn Syndrome (formerly Ehler’s Danlos Syndrome Type IX) from a mutation on ATP7A, a copper importer gene.
It causes two major problems that seemingly fit with what many other patients are finding (connective tissue dysfunction and norepinephrinergic neuron suppression due to DBH deficiency). I wouldn’t be surprised if it’s causing AAI/CCI as well due to dysfunctional prolyl hydroxylase enzyme activity and this is causing chronic PDH suppression somehow. I do have the trademark “horn” where you can feel a bony protuberance in the back of the skull. Food for thought that my base cause may be slightly different than y’alls. The Wikipedia for OHS is an interesting read though especially with all the EDS talk lately:

https://en.m.wikipedia.org/wiki/Occipital_horn_syndrome

 

[ScottTriGuy]

The Wikipedia for OHS is an interesting read though especially with all the EDS talk lately:

https://en.m.wikipedia.org/wiki/Occipital_horn_syndrome

Interesting, I have a 'horn' on the back of my skull too - just assumed everyone did.

From Wiki:

"...whereas one patient has survived to age 57."

Gulp.

 

[SlamDancin]

@sb4 @ScottTriGuy @pattismith @mariovitali

Since this thread is all over the place already, I found the complete report sent to me by the Lights Group and I figured I’d share.

Kathleen Light included this note:

“We think your results and the those of the group as a whole support our hypothesis that the combination of gene variants that might lead to ME/CFS include those that can induce mitochondrial deficiency together with others that can cause autoimmunity that persists too long. Different variants can accomplish these 2 problems, so not everyone will have the exact same gene profile--just similar functional targets. The specific gene variants involved may contribute to other symptoms that some patients experience and others do not (liver problems, joint hyper-mobility, POTS, orthostatic intolerance, IBS, muscle pain and weakness, etc).”

Information on each gene’s function is drawn from GeneCards and Malacards websites. rs numbers are provided for gene variants that have previously been identified to confirm that the variant is an established one. Numbers with colons show the variant’s location on the mitochondrial (MT) DNA or on the specific chromosome (examples are X: for X chromosome and 14: for chromosome 14).

Mitochondrial Complex 1 DNA Gene Variants (both rare)
MT-ND1 line 42455 rs2853516 MT:3316
MT-ND2 line 42491 rs3021088 MT:5460
Mitochondrial complex 1 activity is the first step in the generation of energy from electron transport leading to production of ATP. Mitochondria create more than 90% of the energy for all bodily functions.

Chromosomal DNA Gene Variants
NAD Pathway gene variants
In energy generation/metabolism, NAD (nicotinamide adenine dinucleotide) transfers electrons between sequential redox reactions, and thus is of major importance in the energy production pathways.
NQO1 deleterious variant in 13 CFS versus 3 Others (7% vs 3%)
Member of NAD family, NAD quinone dehydrogenase, with roles in energy metabolism. Malacards links variants to Tardive Dyskinesia signaled by neurological and motor side effects of neuroleptic drugs.
ATP7A line 43071 deleterious/possibly damaging n=21 CFS 12% n=6 Other 7%. X:78013005 rs2227291 Functions in transport of metals especially copper across membranes. Patients with deficient ATP7A may be less able to adequately absorb and use copper, a micronutrient required for energy metabolism, catecholamine biosynthesis and connective tissue formation. They may also have problems with iron metabolism. Genetic variants or decreased expression of ATP7A may be related to an adult-onset distal motor neuropathic condition that resembles Charcot Marie Tooth disorder, and also to Ehlers Danlos Syndrome Type 9 (aka occipital horn syndrome) a connective tissue disorder characterized by hyperelastic and bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, and multiple skeletal abnormalities, and to Wilson disease in which liver and nervous system problems develop as copper accumulates when it cannot be excreted well from the liver into the bile. (See GeneCards and Malacardswebsites)
SERPINA1 line 12948 n=16 CFS 9% n=3 Other 3% 14:94378506 rs1303 .
2nd SERPINA1 variant Line 12953 n=11 CFS 6% n=3 Other 3% 14:94381078 rs6647
Serine protease inhibitor whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. Defects in this gene can cause emphysema or liver disease associated with alpha-1 anti-trypsin deficiency. Symptoms may include shortness of breath and wheezing, repeated infections of the lungs or the liver, yellow skin, fatigue, rapid heartbeat when standing, vision problems, and weight loss. However, some people with AATD may not have any problems.
IFITM2 line 6085 CFS n=76 (43%) versus Other n=23 (25.5%) 11:308290 rs1058900
Interferon -induced antiviral protein which inhibits the entry of viruses to the host cell cytoplasm, preventing subsequent viral fusion and release of viral contents into the cytosol. Active against multiple viruses, including influenza A virus, SARS coronavirus (SARS-CoV), Marburg virus (MARV), Ebola virus (EBOV), Dengue virus (DNV), West Nile virus (WNV), human immunodeficiency virus type 1 (HIV-1) and vesicular stomatitis virus (VSV).
GTPBP6 line 42680 in 60 CFS versus 22 Others (34% vs 24%) no rs# X:315276
GTP binding protein on X/Y chromosomes, role in carbohydrate pathways.

Note: This report complete 0n 12/05/18 may be updated if our full sample data analysis later identifies other gene variants which have an increased frequency in ME/CFS patients and which this individual patient may carry.

 

[SlamDancin]

@ScottTriGuy That’s interesting you have that “horn” as well. I’d like to know if more people have that because I was starting to get pretty freaked out lol

 

[SlamDancin]

Interesting, I have a 'horn' on the back of my skull too - just assumed everyone did.

From Wiki:

"...whereas one patient has survived to age 57."

Gulp.

It’s also been suggested that I’m going down a hypochondriac rabbit hole with some of these results so I don’t want to scare anyone. My bad

 

[Mary]

This can only occur if the kidneys are high pH. If they are low pH, the citrate moves the other way and is scavanged from the urine and instead acid loads are dumped there. This leaves less citrate to bind calcium and possibly more oxalate in the kidneys.

When I first started taking potassium some 9 nears ago (can't believe it's been that long! ), I was taking potassium citrate. However, I rather quickly developed either an irritated bladder or bladder infection. I did some reading and found one reference to potassium citrate causing these issues. I stopped it (switched to potassium gluconate) and the problem went away. So I've stayed away from potassium citrate ever since. Now I'm wondering if perhaps my kidney pH might have been a factor in this issue. I have no idea what my kidney pH was but perhaps it was low. Overall I tend to be acidic.