Acid-Base disturbances, low bicarbonate?

[PinkPanda]

Hello!

I've been looking into the issue of bicarbonate and carbon dioxide levels lately.

I noticed that the citric acid cycle can produce carbon dioxide/CO2 (picture here), which can be converted to bicarbonate (HCO3−):
H2O + CO2<--> HCO3− + H+

I find interesting that HCO3−/bicarbonate is a cofactor in important processes like gluconeogenesis, ammonium excretion by the urea cycle, AMP and GMP synthesis in the purine synthesis (AMP can be converted to ATP, which is an important energy unit. GMP can be converted to GTP, which is needed for G protein function).

So I think low citric acid cycle function might reduce CO2 production, which might then lower HCO3−/bicarbonate. Lactic Acidosis for example can be associated with low bicarbonate and low total CO2 in the blood (reference).

Bicarbonate is a base and is part of the bicarbonate buffer system. I also think that the levels of bicarbonate and carbon dioxide might be influenced by levels of acids like lactic acid or bases like ammonium, because then the buffer should shift in one direction.
Does anyone have any knowledge on this?

Is there any proof, any study on people with ME/CFS producing more lactate? Or is that only part of some theories?
Does anyone have any experience or tests done on low carbon dioxide, low bicarbonate or disturbances in the acid-base balance?
If anyone has any thoughts or experiences to share, please share

 

[gregh286]

KDM does lactate test.
I was X2 over top of normal range. Definetly lactic, you can feel it in your legs.
does it not come from anaerobic energy production?

 

[BadBadBear]

At one point I went into acidosis early in the course of my disease. The doctors were scratching their heads as I got sicker and sicker. I finally started taking bicarb (eventually potassium bicarb) and got better. I still have to take it at times.

I have learned that for me, the feeling that I need betaine to digest meat means that I need bicarb. I think my body will not produce acid for digestion when I am low on bicarb, as a protective mechanism.

If I have enough bicarb, I don't need betaine. It is counter intuitive, but after being so sick with acidosis, it became very clear that I must have adequate buffer intake.

 

[GreenBlanket]

If you haven't come across it already, you might learn about the Bohr effect. The Bohr effect describes the relationship between pH and the oxygenation of body tissues. https://en.wikipedia.org/wiki/Bohr_effect Oxygenation is one of the many things studied in CFS.
Also Cort Johnson said that at a 2014 CFS conference, a young researcher was studying the relationship between pH and CFS. I know nothing more about it than that, ...just that a researcher considered it worthy of research.

 

[PinkPanda]

Thankyou for your replies, they are very helpful!

does it not come from anaerobic energy production?

Yeah, right, it does. The topic is so complicated, I got a bit confused.

@BadBadBear How do you take the bicarbonate now? As baking soda?

The Boehr effect describes the relationship between PH and the oxygenation of body tissues. https://en.wikipedia.org/wiki/Bohr_effect

Thankyou, I didn't know about that.

 

[aquariusgirl]

Follow

 

[Gondwanaland]

If I have enough bicarb, I don't need betaine.

Indeed

https://en.wikipedia.org/wiki/Pancreatic_juice
Pancreatic juice is alkaline in nature due to the high concentration of bicarbonate ions. Bicarbonate is useful in neutralizing the acidic gastric acid, allowing for effective enzymic action.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726758/
Biotin-dependent carboxylases catalyze the fixation of bicarbonate in organic acids and play crucial roles in the metabolism of fatty acids, amino acids and glucose. Carboxylase activities decrease substantially in response to biotin deficiency.

 

[BadBadBear]

@Gondwanaland - ooh, good find. Sounds like I could try increased biotin along with bicarb?

@PinkPanda - I take potassium bicarb. I need extra potassium, and do regular bloodwork to track my levels. So potassium bicarb kills two birds with one stone for me.

 

[PinkPanda]

Found the study, still trying to understand it.

Abnormalities in pH handling by peripheral muscle and potential regulation by the autonomic nervous system in chronic fatigue syndrome

..Whilst there is a common monotonic decrease in proton efflux with time in all the controls, in agreement with previous work in healthy controls [31], the time course of efflux in CFS/ME patients is not uniform and does not decrease monotonically. CFS/ME patients had significant suppression of proton efflux immediately postexercise (Fig. 1a), the time taken to reach maximum proton efflux was significantly prolonged in CFS/ME patients (Fig. 1b), and the magnitude of maximum proton efflux was reduced compared to the controls (Fig. 1c). These findings suggest that there is significant impairment of both the level of proton excretion in recovery phase following exercise, and a prolongation of the kinetics of that recovery. In simple terms, the CFS/ME patients recover substantially more slowly than normal controls. As has been previously described in healthy controls of all ages [31], the rate of maximum proton efflux showed a strong inverse correlation with nadir pH following exercise (Fig. 2). This is a physiological response whereby the level of acidosis regulates the resulting stimulation of proton efflux tailoring to the need for that recovery. ...

Some other infos, I've picked up:

Acids promote production of H+/ protons in watery solution.
Lactic Acidosis is accompanied by an increase in protons. I am not sure how that relates though, as mitochodnria are not aqueous/ water solution (?). Maybe the proton increase is related to mitochondrial function. The citric acid cycle for example produces protons.
High NADH/H+ might raise protons??

Two infos on oxygen saturation

The binding affinity of hemoglobin to O2 is greatest under a relatively high pH.

low CO2 levels in the blood stream results in a high pH, and thus provides more optimal binding conditions for hemoglobin and O2.

https://en.wikipedia.org/wiki/Oxygen–hemoglobin_dissociation_curve

So 2 factors that reduce oxygen binding to hemoglobin are lower, more acidic pH, like with more lactate
and higher CO2 ,which also lowers pH.

In general, my current direction is that shifts in metabolism can cause shifts in pH. More lactate, more acidic, more ammonium for example causes more alkaline/ base pH.
These shifts might influence CO2/HCO3 balance. Additionally, low mitochondrial function might reduce production of CO2.
Since CO2 and HCO3- (bicarbonate) are both cofactors in important pathway (example: CO2 needed for starting fatty acid synthesis and for synthesis of purines, bicarbonate cofactor for pyrimidine synthesis, ammonium excretion in urea cycle), low or shifted levels might reduce these pathways.

I think there might be individual differences, some people might have low CO2, some low oxygen saturation, some low HCO3, depending on how the metabolism is shifted. Don't know what case would be most common in ME/CFS.

Also, more acidic pH and more CO2 might impact oxygen saturation, although that is probably not an issue for most people with ME/CFS (?).

I was wondering, if 'something in the serum' found in Dr Davis research might in some form relate to pH and these metabolites, changes in levels of H+, CO2, HCO3-, ..

 

[PinkPanda]

Metabolic acidosis
Decreased HCO3-, due to increased acid or loss of bicarbonate

• Alcoholic ketoacidosis
• Diabetic ketoacidosis
• Kidney failure
• Lactic acidosis
• Toxins – overdose of salicylates (aspirin), methanol, ethylene glycol
• Gastrointestinal bicarbonate loss, such as from prolonged diarrhea
• Renal bicarbonate loss

Metabolic alkalosis
Increased HCO3-, due to loss of acid or gain of bicarbonate

• Diuretics
• Prolonged vomiting
• Severe dehydration
• Diseases that cause loss of potassium
• Administration of bicarbonate, ingestion of alkali

https://labtestsonline.org/conditions/acidosis-and-alkalosis

 

[PinkPanda]

My current understanding (vague, possibly wrong):

Acid and Base- balances seem to be more complex in the body than in standard chemistry and watery solution, as production of acids, bases and protons seems connected to how much some pathways function.


Shifted metabolisms (this sounds so nice):
Whatever the cause, the metabolism might shift to producing more lactate from pyruvate (pyruvate+ NADH/H+ -> lactate+ NAD+), for example if the pyruvate dehydrogenase or respiratory chain is inhibited.

High lactate is generally not good, but might support some functions in the energy metabolism. First of all, this reaction can reduce too high NADH/H+. Lactate can also be used for glycogen synthesis (?), and glycogen can be converted back to glucose. So this prevents low-blood sugar and the glucose might be used for energy production by being broken down in the glycolysis, which produces ATP and NADH/H+ or by being converted to fat and the fats being broken down.

If the respiratory chain or pyruvate dehydrogenase are inhibited, the metabolism could for example shift to produce more energy with lactate instead. This still doesn't seem to compensate the inihbited parts of the energy metabolism and might cause symptoms, like from high lactate,..

This is just an example of how metabolisms might shift, if certain parts are inhibited. Someone else might for example have thyroid dysfunction and compensate with strong carbohydrate or amino acid metabolism. These shifts might be accompanied by shifts in pH.

I think you can also see these shifts somewhat in mostly healthy people. Some people get their energy from eating a lof of fats, others need a lot of carbohydrates. Everyone has a basic metabolic balance.


The probably most common CFS case:

High lactate
Low citric acid cycle function
Low/ acidic pH
Low HCO3-, low CO2

Coming back to the study from two posts above:

There is a close relationship between the degree of acidosis and proton efflux suggesting a closely regulated process: this has been observed in controls in other studies [31], and the pH changes observed in the control group are also in agreement with similar studies [27, 32]. In CFS/ME patients this relationship is lost

CFS/ME patients had significant suppression of proton efflux immediately postexercise (Fig. 1a), the time taken to reach maximum proton efflux was significantly prolonged in CFS/ME patients (Fig. 1b), and the magnitude of maximum proton efflux was reduced compared to the controls (Fig. 1c).

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2009.02160.x/full

Biochemistry of exercise-induced metabolic acidosis

The development of acidosis during intense exercise has traditionally been explained by the increased production of lactic acid, causing the release of a proton and the formation of the acid salt sodium lactate. On the basis of this explanation, if the rate of lactate production is high enough, the cellular proton buffering capacity can be exceeded, resulting in a decrease in cellular pH. These biochemical events have been termed lactic acidosis.

This belief has led to the interpretation that lactate production causes acidosis and, in turn, that increased lactate production is one of the several causes of muscle fatigue during intense exercise.

http://www.physiology.org/doi/full/10.1152/ajpregu.00114.2004

My understanding: If you exercise, your body switches to anaerobic respiration and increased production of lactate from pyruvate, the pH gets more acidic. In the recovery phase, there is an increase in proton /H+ efflux and the pH gets restored. The body probably shifts back to aerobic respiration and increases function of citric acid cycle and reduces lactate production again.
The increase in proton efflux does not happen sufficiently in ME/CFS. There is reduced proton efflux.

Protons are produced in energy processes like the citric acid cycle, where NAD+ is converted to NADH and H+. Maybe too low citric acid cycle function reduces proton production.
https://upload.wikimedia.org/wikipe...px-Citric_acid_cycle_with_aconitate_2.svg.png

I see this as a complex system, where, if certain pathways are increased you have more acid production, or more base production. Low citric acid cycle function might lower H+ production, raise lactate, lower CO2 (also produced in the citric acid cycle). This results in certain metabolic signatures. This might also be responsible for the problems after exercise, with diminished capability to swith back to aerobic respirtion.
(Maybe exercise in ME/CFS is like sugar in diabetes, it increases an already existing problem of anaerobic respiration.:thumbdown:?? Shifts even more in the wrong direction)

The relevant question is, what causes these shifts and how do you relieve them. Also, apart from the shifts, there might simply be a common problem of some reduced processes and low energy.
I am unsure on how much understanding this better will give an answer on what the cause is. We'll see.
....long post
I'm still trying to get the whole acid-base issue, so maybe I've interpreted some stuff wrong..

 

[PinkPanda]

Experimental evidence suggests that nucleoside analogues induce l-carnitine deficiency [1], which may contribute to the occurrence of lactic acidosis. We report the successful use of l-carnitine to treat severe lactic acidosis and hepatic failure in a patient treated by nucleoside analogues.

https://journals.lww.com/aidsonline...ne_as_a_treatment_of_life_threatening.29.aspx

Enduarance training or administration of T3 to hypothyroid rats markedly improve their exercise performance and elevate TLA, however, T3 treatment markedly increases maximal and submaximal LA levels.

LA= blood lactate
https://www.researchgate.net/public...rcise_tolerance_and_lactate_threshold_in_rats

Q10 deficiency can inhibit the respiratory chain and consequently the pyruvate dehydrogenase. I don't really see Q10 as a viable supplement at the moment. Q10 is synthesized in the cholesterol biosynthesis, which requires NADPH/H+, acetyl-CoA and ATP, and with SAMe.

 

[PinkPanda]

What causes acidosis?

There are different opinions on what the cause of acidosis during exercise is.

In 2004 Robergs et al. maintained that lactic acidosis during exercise is a "construct" or myth, pointing out that part of the H+ comes from ATP hydrolysis (ATP4− + H2O → ADP3− + HPO2−
4 + H+), and that reducing pyruvate to lactate (pyruvate− + NADH + H+ → lactate− + NAD+) actually consumes H+.[19] Lindinger et al.[20] countered that they had ignored the causative factors of the increase in [H+]. After all, the production of lactate− from a neutral molecule must increase [H+] to maintain electroneutrality. The point of Robergs's paper, however, was that lactate− is produced from pyruvate−, which has the same charge. It is pyruvate− production from neutral glucose that generates H+:

https://en.wikipedia.org/wiki/Lactic_acid#Exercise_and_lactate

pH describes the invert concentration of protons/H+ in a solution. In a high pH/base solution, concentrations of protons are low, in an acidic solution/low pH, proton concentrations are high. So the high proton concentrations make the pH acidic.

I agree that high lactate might not cause acidosis, but rather be a side-effect. The conversion from pyruvate to lactate binds two protons, so lactate is rather a mechanism of binding excess NADH/H+ protons and raising NAD+ levels.
pyruvate + NADH/H+ <-> lactate + NAD+

I don’t really get how ATP to ADP releases a proton. Whether a proton is released when ATP reacts to ADP, seems to depend on how many protons are being bound in phosphate.

Here no proton is left over http://www.genome.jp/dbget-bin/www_bget?rn:R00086 as phosphate takes up one H+ to form H3PO4/Orthophosphate (C00009). There are different forms of phosphate that make up the phosphate buffer system.

• In strongly basic conditions, the phosphate ion (PO3−4) predominates,
• In weakly basic conditions, the hydrogen phosphate ion (HPO2−4) is prevalent. * In weakly acidic conditions, the dihydrogen phosphate ion (H2PO−4) is most common.
• In strongly acidic conditions, trihydrogen phosphate (H3PO4) is the main form.

https://en.wikipedia.org/wiki/Phosphate

It seems to me at the moment that whether a proton is released when ATP is converted to ADP depends on the pH of the cell and on which form of phosphate is prevalent. In neutral to acidic conditions phosphate might bind the proton to dihydrogen- or trihydrogenphosphate. So I don’t know about the theory of the ATP to ADP reaction being the cause of high proton release and acidosis during exercise.

The most obvious thing to me that produces a lot of H+, is NADH/H+ production in energy processes like the citric acid cycle.

During anaerobic exercise low oxygen inhibits the function of the respiratory chain. This might increase NADH/H+, because NADH/H+ usually transfers its electrons and protons into the oxidative phosphorylation and converts back to NAD+. High NADH/H+, acetyl-CoA or ATP can inhibit the pyruvate dehydrogenase, so the high NADH/H+ might inhibit the pyruvate dehydrogenase and increase lactate production.

This reaction in the respiratory chain complex IV can actually bind protons dependent on oxygen to form water:
O2 + 4H+ + 4e- -> 2H2O

Picture here:
https://de.wikipedia.org/wiki/Cytochrom-c-Oxidase#/media/File:Cytaa3simple.svg
(They also have additional 4 protons in the picture which are sent through the complex into the outer mitochondrial membrane)

That’s why I think increased activity of the respiratory chain might raise pH/make it less acidic, by transferring protons from NADH/H+ and binding them in water.

So increased lactate production seems to be a reaction and can bind lower NADH/H+ and raise NAD+. In exercise the body uses up a lot of ATP, especially by the myosin ATPase and calcium ATPase. These ATPases are associated with the relaxation-contraction cycle of muscles during exercise.
(https://books.google.se/books?id=q8aVVxGjYnEC&lpg=PP1&hl=de&pg=PP1#v=onepage&q&f=false)

The body can produce ATP in anaerobic system in the glycolysis, which produces ATP and NADH/H+. The glycolysis needs NAD+, and lactate formation can help raise NAD+ in comparison to NADH/+ to keep the glycolysis going.

I’m still thinking on the mechanisms in ME/CFS, but I found this interesting.


ETA: Additional thought, I don't know how easily NADH/H+ passes into the blood, while lactate is transported in the blood a lot, since it can form pyruvate again in the liver (Cori Cycle). So maybe the problem in lactic acidosis is that high levels of protons are being produced in energy processes and not metabolized further, but the formation of lactate makes the whole thing more dangerous.

Lactate in the blood can then dissociate into lactate- and H+ and this makes the blood pH acidic. Acidic blood pH can for example reduce the oxygen saturation of hemoglobin.

 

[PinkPanda]

Apart from high NADH/H+, ATP and acetyl-CoA, what inhibits the pyruvate dehydrogenase is a lack of cofactors (vitamin B1,B2,B3,B5, alpha lipoic acid, Mg, Ca).

Ca2+ at physiological concentrations was found to regulate dehydrogenase enzymes of mitochondria: glycerophosphate dehydrogenase [5], responsible for shuttling reducing equivalents from cytosolic NADH into mitochondria, and the mitochondrial matrix dehydrogenases pyruvate dehydrogenase (PDH) [6], isocitrate dehydrogenase (ICDH)[7] and oxoglutarate (or α-ketoglutarate) dehydrogenase (OGDH) [8]. Thus Ca2+ stimulates both glycogen breakdown and glucose oxidation leading to increased ATP supply.

https://www.sciencedirect.com/science/article/pii/S000527280900036X

Calcium signaling has been implicated as a mechanism that enables the body to increase energy production when requirements rise like during exercise.

One enzyme that is important for releasing calcium from the endoplasmatic reticulum is phospholipase C. It is activated by G proteins which use GTP/guanosine triphosphate.

Importance of breakdown of odd-numbered fatty acids and certain amino acids via propionyl-CoA to succinyl-CoA

Odd-numbered fatty acid rests and the amino acids valine, isoleucine, threonine and methionine can be broken down to propionyl-CoA and then succinyl-CoA dependent on cofactors like adenosylB12/hydroxo.

Succinyl-CoA enters the citric cycle where the first two reactions are:

1) succinyl-CoA+ GDP+Pi-> succinate + GTP + CoA-SH
2) succinate +FAD -> fumarate + FADH2

2) is coupled to the respiratory chain complex II and FADH2 then transfers its 2H+ and 2e- to QH2: picture here

I think the balances of some substances (like ATP to NADH/H+ to GTP,..) are important and propionyl-CoA to succinyl-CoA increases GTP and FADH2 but only forms one NADH/H+ in the citric acid cycle. If you take the same route with pyruvate in the citric acid cycle, you get 4 NADH/H+ on one GTP and one FADH2. If high NADH/H+ is a potential problem by inhibiting the pyruvate dehydrogenase and increasing lactate production, the propionyl-CoA pathway produces relatively little NADH/H+.

Maybe this pathway can keep aerobic systems going longer by increasing GTP and calcium signaling, but not NADH/H+ that much.

My current idea is that some substances can accumulate and cause a jam, like high (cystosolic?) NADH/H+ or high acetyl-CoA, if other processes are functioning too low. Low GTP might work like that, inhibiting calcium signaling and I hope that the propionyl-CoA pathway might be a relevant pathway to get things moving along.
A typical example of such a pathway would be an inhibited repiratory chain in genetic disorders.



Calcium excretion can also increase glycerophosphate dehydrogenase activity.

Glycerol 3-phosphate dehydrogenase

NADH/H+ cannot simply pass through the mitochondrial membrane from cytosol to mitochondria. There are two shuttles that help transport NADH/H+ across the mitochondrial membrane the malate-aspartate-shuttle and the glycerol 3-phosphate shuttle: https://de.wikibooks.org/wiki/Bioch..._Druckversion#Das_Glycerin-3-Phosphat-Shuttle

Glycerol-3 phosphate can take up two electrons and two protons from NADH/H+. Glycerol 3-phosphate can transfer the 2H+ and 2e- to FAD in the mitochondria forming FADH2.

Picture here: https://en.wikipedia.org/wiki/Glycerol-3-phosphate_dehydrogenase#/media/File:GPDH_shuttle.png

This process reduces NADH/H+ back to NAD+ in the cytosol and increases FADH2 in the mitochondria which can transfer its 2H+ and 2e- to Q10 forming QH2. This can increase ATP production.

This might be one process that is beneficial during exercise, as NADH/H+ is reduced and it can’t form lactate anymore and ATP is increased which is important for higher ATP requirements during exercise. More GTP in the citric acid cycle might increase this process due to more calcium release.


pH and ME/CFS

At the moment I think that missing cofactor like calcium and high NADH/H+ in the cytosol due to defect transfer to the mitochondria might raise lactate production. There is too little citric acid cycle function in general which causes too low proton and CO2 production in the citric acid cycle. This might also be a reason why there was a too low increase in protons after exercise in ME/CFS patients (study a few posts up). Inhibited pyruvate dehydrogenase and low citric acid cycle function caused less conversion back from lactate to pyruvate (produces protons/ NADH/H+) and less activation of citric acid cycle proton production, while healthy people switched back to the aerobic system more.

Also, I think citric acid cycle function might be lower in ME/CFS compared to genetic defects in the respiratory chain. People with these defects might have higher NADH/H+ and develop lactic acidosis more.

Low HCO3- might be due to elevated lactic acid and due to low carbon dioxide production in the citric acid cycle. I think the processes that use HCO3- might also be reduced so I don’t know if an actual deficiency is visible, because it isn’t used up (?).
Processes that use HCO3-: Fatty acid synthesis, pyruvate carboxylase for pyruvate to oxaloacetate in gluconeogenesis, conversion from propionyl-CoA to succinyl-CoA (pathway here, although one enzyme (KEGG, wikipedia) is wrong, uses HCO3- not CO2), pyrimidine synthesis, ammonium breakdown (carbamoylphosphate synthesis), breakdown of leucine.



I also liked this picture on page 165 figure 9.1

https://books.google.se/books?id=q8aVVxGjYnEC&lpg=PP1&hl=de&pg=PA165#v=onepage&q&f=false

It shows the importance of calcium and that branch-chained amino acids are low in muscle fatigue. I thought maybe this supports that amino acids like isoleucine and valine are important in exercise.


I might correct this post, haven't thought it over that much yet.....


Addition:
Even if the respiratory chain doesn't work enough, GTP production alone can raise ATP. The nucleoside diphosphate kinase (NDPK) can transfer a phosphate group from one nucleoside triphosphate to another nucleoside diphosphate:
XDP + YTP ←→ XTP + YDP
ADP + GTP ←→ ATP + GDP

NDPK activities maintain an equilibrium between the concentrations of different nucleoside triphosphates such as, for example, when guanosine triphosphate (GTP) produced in the citric acid (Krebs) cycle is converted to adenosine triphosphate (ATP).[1] Other activities include cell proliferation, differentiation and development, signal transduction, G protein-coupled receptor, endocytosis, and gene expression.

https://en.wikipedia.org/wiki/Nucleoside-diphosphate_kinase

This might help balance ATP and calcium. If ATP is too low and GTP is too high, calcium might rise too much. Then GTP can raise ATP, which can transfer calcium back out of the cell and into the endoplasmatic reticulum with ATPases.
This might be a special feature of this pathway/ GTP, in comparison to increasing function of the inositol triphosphate pathway, which raises calcium more in general.

 

[PinkPanda]

Calcium as an Enzyme Cofactor

Enzyme location: Cytosol, Glycosome or extracellular

Glucose metabolism

· Activating glycogen phosphorylase, which converts glycogen to glucose

When the body needs glucose for energy, glycogen phosphorylase, with the help of an orthophosphate, can cleave away a molecule from the glycogen chain. The cleaved molecule is in the form of glucose-1-phosphate, which can be converted into G6P by phosphoglucomutase. Next, the phosphoryl group on G6P can be cleaved by glucose-6-phosphatase so that a free glucose can be formed. This free glucose can pass through membranes and can enter the bloodstream to travel to other places in the body.

https://en.wikipedia.org/wiki/Glucose_6-phosphate​

· Inhibiting glycogen synthase that catalyzes the conversion from glucose derivates to glycogen. Glycogen acts as a glucose store in the liver, which can release glucose into the blood.

The liver enzyme expression is restricted to the liver, whereas the muscle enzyme is widely expressed. Liver glycogen serves as a storage pool to maintain the blood glucose level during fasting, whereas muscle glycogen synthesis accounts for disposal of up to 90% of ingested glucose. The role of muscle glycogen is as a reserve to provide energy during bursts of activity.

Glycogen synthase concentration is highest in the bloodstream 30 to 60 minutes following intense exercise.

https://en.wikipedia.org/wiki/Glycogen_synthase​

· Inhibition of pyruvate kinase, which converts phosphoenoylpyruvate to pyruvate in the glycolysis. Phosphoenoylpyruvate can then instead be used for gluconeogenesis, converting back to glucose.​

Cytosolic/ extracellular (?) calcium plays an important role in glucose metabolism, increasing glucose release into the blood, gluconeogenesis and reducing glycogen storage in the liver.

Other metabolisms

· Phospholipase A2 cofactor (cytosolic and extracellular): cleaves phospholipids releasing arachidonic acid. A step in the conversion of phosphatidylcholine to choline.

· Phospholipase C cofactor

· Myosin light chain kinase:
ATP + [myosin light chain] = ADP + [myosin light chain] phosphate (KEGG)
This enzyme is important in muscle contraction.​

· Cofactor in cholesterolbiosynthesis (Isopentenylpyrophosphate Delta-isomerase, pathway here). Important step in synthesis of Q10, vitamin D, cholesterol, cortisol and from cortisol bile acids and steroid hormones in the cholesterolbiosynthesis.

· NAD(P)H oxidase (KEGG)

NAD(P)H oxidase is a membrane-associated enzyme that catalyzes the production of superoxide– a reactive free radical– through a one electron transfer from NAD(P)H (NADH or NADPH) to oxygen as the electron acceptor. It is considered one of the major sources of superoxide anions in humans as well as bacteria, used in oxygen-dependent killing mechanisms for invading pathogens.

https://en.wikipedia.org/wiki/NAD(P)H_oxidase

NAD(P)H oxidase is involved in the immune response to bacteria and fungi. It produces H2O2/ hydrogen peroxide. Hydrogen peroxide is also a cofactor in thyroid hormone synthesis which makes NAD(P)H oxidase activity a regulator of thyroid hormone synthesis

· Adenylyl Cyclase: a number of isoforms are stimulated by calcium (reference). This enzyme converts ATP to cAMP. cAMP is an important messenger in the cells.
​

Enzyme location: Mitochondria

· Pyruvate dehydrogenase, it can be inhibited by calcium loading though (reference)​

· NAD isocitrate dehydrogenase and α-ketoglutarate dehydrogenase (enzymes in the citric acid cycle)​

· Glycerol 3-phosphate dehydrogenase (more info on its functions above)​

There are more calcium enzymes, these currently seem most relevant to me. A few more here https://en.wikipedia.org/wiki/Category:Calcium_enzymes
If I find more calcium enzymes that might be important, I’ll edit. I’m still getting an overview.

I think too high and too low calcium levels in cytosol, extracellular and in the mitochondria can be problematic. I am trying to understand how dysregulation of calcium in different places might affect NADH/H+ in cytosol and mitochondria, lactate, bicarbonate and proton concentrations.

I think I have a tendency for low calcium (cytosol, blood?) and vitamin D at the moment and need to fix that somehow, otherwise other supplements will only end up lowering my calcium levels more.
All these effects of high and low blood, mitochondrial and cytosolic calcium seem to relate to calcium signaling and not resolve with calcium or vitamin D supplements. Calcium supplements can be problematic as they can raise calcium too much and lead to calcium loading/ prolonged elevated calcium.


Another thought, calcium can be released into the cytosol and mitochondria via stimulating the inositol triphosphate receptor. This ensures a certain calcium level inside the cell, but might at the same time cause more issues with too high calcium and calcium loading than if you raise GTP or ATP.
ATP reduces cytosolic calcium by transporting calcium back out of the cytosol with ATPases and GTP can increase calcium excretion, but also lower calcium again by raising ATP level (via nucleoside diphosphate transferase post above).

So stimulating the inositol triphosphate receptor can increase important calcium-dependent processes, but if it leads to calcium loading, might also have bad effects like inhibiting the pyruvate dehydrogenase and raising lactate. Although lactate is not only bad as it can support gluconeogenesis and glycogen-stores in the liver.

 

[LINE]

Buffering agents or bicarbonates are the body's natural ways of balancing. Too little buffering allows acid accumulation. Too much acid then the energy levels fall, pain increases and other things such as brain fog. Magnesium and potassium are the big players as is sodium.

Lactic acid build up likely due to stressors which include immune activation.Too much calcium will inhibit magnesium, magnesium is lost under stress. Sodium bicarbonate (baking soda) is very alkaline and will neutralize the acids quickly, this is one of my great helps. You can purchase pH paper to monitor levels (Hydrion 5.5 to 8.0)

B vitamins play key roles in metabolism and too are lost under stress.

 

[LINE]

You could also phrase it as too much acid is a sign of metabolic inefficiency. The inefficiency would likely revolve around 1/ nutrient deficiency or increased nutrient needs (likely biological stress, see #2 and #3) - increased stress responses due 2/ immune activation (viral, bacterial, parasitic or other pathogens) 3/ increased toxin loads*.

*increased toxin loads can come from environmental exposures (chemicals), also from immune activation in which the immune system produces very toxic substances (superoxides, toxic nitrogen compounds) and decreased methylation (nutrient deficiency). Toxins put burdens on the immune system which could weaken immunity or skew the immune system meaning it will misfire.

 

[sb4]

Great posts @PinkPanda keep it up. So if I am understanding this correctly, a higher fat diet could be helping our symptoms by keeping NADH/H+ low due to increased FADH2 usage; this leads to less acidic cytosol, less pyruvate dehydrogenase inhibition, less lactate production, and more mitochondrial oxidation.

@LINE You say sodium bicarbonate is one of your big helps. What effects does it give you? I am interested as before I thought it wouldn't help me as I have gastroparesis (probably low stomach acid) but another poster said paradoxically this helps the issue.

 

[LINE]

I can always feel the toxicity building (and has reduced as I addressed the infection(s) and directed nutritional needs)), when the toxicity builds then I use sodium bicarbonate. This clears the toxicity and things turn around for me fairly quickly, energy production comes back up, pain diminishes. Assuming that the toxicity is high, expect runs to the loo

@PinkPanda - sorry if I hijacked the thread.

 

[nanonug]

Recently I posted about Bicarbonate and Mitochondrial Oxidative Phosphorilation. That post provides an alternative (hypothetical) explanation of why bicarbonate may help people with SEID.