high lactate levels aerobic glycolysis , Ron Davis mystery molecule is 2,3dpg i think

phillybadboy

New Member
This is my guess of what is causing chronic fatigue syndrome . In the muscle and brain cells of cfs patients there is higher than normal oxidative stress , there is upregulation of the antioxidant system , and when there is demand for atp there is aerobic glycolysis . the genes and enzymes involved in antioxidant system is upregulated the enzymes involved in aerobic glycolysis is upregulated . Normally PKM1 (pyruvate kinase) is highly expressed in muscle and brain . I believe in cfs PKM2 is higher than normal . activity of PKM2 is lower than PKM1 so this allows diversion of glucose into the pentose phosphate pathway for antioxidant system . Higher than normal PKM2 in dimeric or monomeric form translocates to the nucleus and inhibits the activity of p53 . p53 activity is important for oxidative phosphorylation (sco2) . Lower levels of p53 makes means lower levels of atp production in mitochondria . When the cfs patient is resting lactate levels are lower than normal people because the PKM2 expression less pyruvate is produced to become lactate(PKM1 is normally highly expressed and has higher activity) , when the cfs patient is active lactate levels are higher than normal people , this is because in cfs p53 is lower so oxidative phosphorylation is lower ( mitochondrial atp production is inhibited) so the cell makes more energy through aerobic glycolysis , more glycolysis means more lactate.
I think Ron Davis mystery molecule is 2,3dpg . In Ron Davis study they did studies in mononuclear cells and found possibly lower levels of glycolysis . I think with PKM2 expression in muscle , the lower activity of PKM2 results in build up glycolytic intermediates ( 2,3dpg and others) . 2,3dpg is released out of muscle into blood stream and is taken up by mononuclear cells . 2,3dpg inhibits glycolytic enzymes hk , gapd, pfk , this results in lower pyruvate production . When Ron Davis adds pyruvate to the cells they behaved normally this means oxidative phosphorylation is normal in these mononuclear cells . Just the substrate (pyruvate ) needed for oxidative phosphorylation is low . I think the abnormalities seen in Ron Davis mononuclear is caused by 2,3dg which is just a downstream effect of what is the actual cause of cfs in muscle and brain , in other words if we were to clean up the 2,3dpg we would get the mononuclear cells to behave normally , but you would still have cfs , because the actual cause of cfs in muscle and brain is not 2,3dpg , it is actually the upregulation of the antioxidant system, the lowering of oxidative phosphorylation and the increase in aerobic glycolysis . I think the change activity or expression of these genes or enzymes are causing these problems , nrf2 (upregulated ) important for antioxidant defense , affects glutamine metabolism , there is studidies showing more glutamine metabolism , PKM2 (upregulated ) important for antioxidant system , important for aerobic glycolysis, p53 (downregulated ) very important for oxidative phosphorylation , cytochrome c oxidase .
 

dejurgen

Well-Known Member
Hi Phillybadboy,

How did you came to the idea that 2,3 DPG might be increased in the blood? Issie pointed me before to your post but I couldn't see that 2,3 DPG is more commonly called 2,3 BPG https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid. It sure would be easier if a single molecule didn't had many different names :confused:.

It is quite interesting that you mention 2,3 DPG likely being the thing to be too high in the blood, as 2,3 DPG (aka 2,3 BPG...) is according to https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid:

"2,3-BPG is present in human red blood cells (RBC; erythrocyte) at approximately 5 mmol/L. It binds with greater affinity to deoxygenated hemoglobin (e.g. when the red blood cell is near respiring tissue) than it does to oxygenated hemoglobin (e.g., in the lungs) due to conformational differences: 2,3-BPG (with an estimated size of about 9 Å) fits in the deoxygenated hemoglobin conformation (with an 11 angstroms pocket), but not as well in the oxygenated conformation (5 angstroms). It interacts with deoxygenated hemoglobin beta subunits and so it decreases the affinity for oxygen and allosterically promotes the release of the remaining oxygen molecules bound to the hemoglobin; therefore it enhances the ability of RBCs to release oxygen near tissues that need it most."

So it is (likely) a RBC only intermediate in the glycolitic cycle. Other cells bypass that step. AND more of it inside the RBC increases oxygen release from the RBC towards the tissue. Research more points to the opposite in ME: RBC clinging onto their oxygen.

I have written about it in https://www.healthrising.org/forums/threads/potential-linking-rbc-glycolysis-air-hunger-thyroid-atp-dumping-pregnancy-improvement-and.6236/

That for sure is not me trying to say you are wrong. I too believe oxydative stress is an important part in our disease, and that our bodies try to shift part of the glucose away from glycolysis towards the Pentose Phosphate Pathway. It's that between both of our ideas there seem to be some inconsistencies and wherever they are, getting a closer understanding of what is going on with it might help our understanding of ME.

Kind regards,
dejurgen
 

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