cancer metabolism, gene expression and enzyme expression in cfs skeletal muscle cell

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COMMON PATHWAYS IN CANCER AND CFS

(1) lactate - Lactate levels are high in cancer and cfs .

1. increased lactate secretion by cancer cells sustains non cell autonomous adaptive resistance to MET and EGFR targeted therapies- Moria Apicella

2. Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment- Bo Jiang

3. The aerobic energy production and lactic acid excretion are both impeded in myalgic enecephalomyelitis/chronic fatigue syndrome- Mark Vink

4. Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome-Katarina Lien

5. Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with myalgic encephalomyelitis/chronic fatigue syndrome- Alaa Ghali

(2) aspartate - CFS patients have aspartate levels . Aspartate metabolism is high in cancer cells to be used in biosynthetic pathways.

6. Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients-Chris Armstrong

7. Maintianing cytosolic aspartate levels is a major function of the TCA cycle in proliferating cells-H Furkan Alkan

(3) alanine- Low levels of alanine have been found in cfs. Cancer cells have been found to release alanine which is used for gluconeogenesis.

8. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalomyelitis/chronic fatigue syndrome-Oystein Fluge

9. Release of l-alanine by tumor cells- W Droge

10. Gluconeogenesis from alanine in patients with progressive malignant disease-Christine Waterhouse

11. Altered hepatic gluconeogenesis during L-alanine infusion in weight-losing lung cancer patents as observed by phosphorus magnetic resonance spectroscopy and turnover measurements- Susanne Leij-Halfwerk

(4) glutamine-Low glutamine levels have been found in cfs muscle and cancer.

12. The role of glutamine in the aetiology of the chronic fatigue syndrome-a prospective study-David Rowbottom

13. Plasma free amino acid profiles are predictors of cancer and diabetes development- X Bi C J Henry
''As shown in Table 1 , significant decrease o f Gln (glutamine) was observed in patient with pancreatic cancer, lung cancer,gastric cancer,colorectal cancer, breast cancer, and prostate cancer.''

(5) glutathione- Upregulated GSH levels are observed in cancer and total glutathione levels has been found to be high in cfs skeletal muscle.

14. Role of glutathione in cancer progression and chemoresistance-Nicola Traverso
'' Elevated GSh levels are observed in various types of tumors, and this makes the neoplastic tissues more resistant to chemotherapy.''

15. Glutathione levels in human tumors-Michael Gamcsik

16. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome-Stefania Fulle
'' In this study, we detected oxidative damage to DNA and lipids in muscle specimens of cfs patients as compared to age-matched controls, as well as increased activity of antioxidant enzymes catalase, glutathione peroxidase, and transferase, and increases in total glutathione plasma levels.'' NOTE, here plasma does not mean blood plasma, the authors actually mean intracellular fluid or cytoplasmic fluid

(6) 2,3 dpg- 2,3 dpg levels have been found to be in cfs and cancer.

17. Erythrocyte oxidative damage in chronic fatigue syndrome -Ross S Richards

18. 2,3 diphosphoglycerate, a cellular ageing metabolite-E De la Morena
'' The concentration of 2,3 diphosphoglycerate was increased in whole venous blood of patients with various cancers, including those of breast, ovary, lung and colon , but not rectum, compared to age-matched controls. Higher values, increasing with age, were also found in patients with Hodgkin's disease and other lymphomas. This abnormality is considered to be due to increased synthesis of the metabolite by the tumour tissue.''

(7) NF-kB- NF-kB activation plays a role in cancer and cfs.

19. Nf-kB, an active player in human cancers- Yifeng Xia

20. Not in the mind of lazybones of neurasthenic lazybones but in the cell nucleus. patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta-Michael Maes

(8) p53- p53 activity has been found to be low in cancer and in cfs is suggested to be low.

21. Role of p53 in cell death and human cancers-Toshinori Ozaki

22. Increased nuclear kappa-kB and loss of p53 are key mechanisms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Michael Maes

(9) glycolysis- Glycolysis is upregulated in cancer and cfs skeletal muscle.

23.Energy metabolism of cancer. glycolysis versus oxidative phosphorylation (review)-Jie Zheng
''Unlike normal cells, glycolysis is enhanced and OXPHOS is capacity is reduced in various cancer cells.''

24. skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31p nuclear magnetic resonance spectroscopy- Roger Wong
''These data suggest a defect in oxidative metabolism with resultant acceleration of glycolysis in the working skeletal muscle of cfs patients.''

(10) oxidative phosphorylation- Redued oxidative energy production is found in cancer and cfs skeletal muscle.

23. Energy metabolism of cancer . glycolysis vs oxidative phosphorylation(review)-Jie Zheng
''unlike normal cells, glycolysis is enhanced and OXPHOS capacity is reduced in various cancer cells.''

24. skeletal muscle metabolism in the chronic fatigue syndrome. in vivo assessment by 31p nuclear magnetic resonance spectroscopy-Roger Wong
''These data suggest a defect in oxidative metabolism with a resultant acceleration of glycolysis in the working skeletal muscle of cfs patients

(11) oxidative stress (ROS)- Increased oxidative stress and elevated levels of ROS have been found in cancer and cfs skeletal muscle.

25. Reactive oxygen species. a key constituent in cancer survival-Seema Kumari

16. Specific oxidative alterations in vastus rateralis muscle of patients with the diagnosis of chronic fatigue syndrome-Stefania Fulle
''From these results we hypothesize that in CFS there is oxidative stress in muscle, which results in an increase in antioxidant defenses.''

(12) antioxidant system upregulation- The antioxidant system is upregulated in cancer cells and cfs skeletal muscle cells.

26. ''ROS in cancer therapy. the bright side of the moon-Bruno Perillo
''The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells.''

16. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome.-Stefania Fulle
''From these results we hypothesize that in CFS there is oxidative stress in muscle , which results in an increased in antioxidant defenses.''

(13) lipid peroxidation- Increased lipid peroxidation due to increased ROS has been found in cancer and cfs skeletal muscle.

27. Oxidative stress and lipid peroxidation products in cnacer progression and therapy-Giuseppina Barrera

16. Specific oxidative alterations in muscle of patients with the diagnosis of chronic fatigue syndrome-Stefania Fulle

(14) immune-inflammatory pathways- Activation of immune-inflammatory pathways are found in cancer and cfs.

28. Roles of the immune system in cancer. from tumor initiation to metastatic progression-hugo Gonzalez

29. Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins-Michael Maes

(15) AMPK- Downregulation of AMPK activity is found in cancer and cfs skeletal muscle.

30. Down regulation adenosine monophosphate-activated protein kinase activity. A driver of cancer- Xiaoling He
''AMPK activity is down-regulated in most tumor tissues, compared with the corresponding adjacent paracancerous or normal tissues, indicating that the decline in AMPK activity is closely associated with the development and progression of cancer.''

31. Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome-Audrey E Brown

(16) NRF2- Nuclear factor erythroid 2-related factor 2 (Nrf2) is found to be upregulated in cancer. I haven't found studies regarding nrf2 in cfs muscle but I believe if testing was done Nrf2 being the master regulator of the antioxidant response would be found upregulated as well.

32. Potential applications of nrf2 inhibitors in cancer therapy-Emiliano Panieri

(17) PKM2- Pyruvate kinase m2 (pkm2) expression is upregulated in cancer. Pkm2 reexpresion has been found in some other in other medical conditions example in myotonic dystrophy type 1 (dm1)( in type 1 muscle fibers) .(reference 45.) Increased PKM2 expression has been found in skeletal muscle after burn injury.(reference 46.) Increased pkm2 expression has been found in the hearts of humans with heart failure. (reference 47.) Increased pkm2 expression has been found in hearts after myocardial infarction.(reference 48.) I haven't found any studies regarding pkm2 in cfs muscle but I believe if testing was done pkm2 expression would be found to be upregulated, since pkm2 is required to divert glucose-6-phosphate into the pentose phosphate pathway for increased NADPH production for the upregulated antioxidant system that has been found in cfs skeletal muscle.(reference16.)

33. Pyruvate kinase m2 and cancer. the role of pkm2 in promoting tumorigenesis- Kulsoom Zahra

34. Nrf2 a transcription factor for stress response and beyond-Feng He

35. pkm2, function and expression and regulation- Ze Zhang

36. overexpression of pkm2 promotes mitochondrial fusion through attenuated p53 stability-Haili Wu

37. Pgc-1alpha increases skeletal muscle lactate uptake by increasing the expression of mct1 but not mct2 or mct4-Carley R Benton

38. p53 negatively regulates transcription of the pyruvate dehydrogenase kinase pdk2-Tanupriya Contractor

39. prospective biomarkers from plasma metabolomics of myalgic encephalomyelitis/chronic fatigue syndrome implicate redox imbalance in disease symptomatology- Arnaud Germain

40. ROS-mediated p53 induction of lpin1 regulates fatty acid oxidation in response to nutritional stress-Wissam Assaily

41. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPRAalpha regulatory pathway- Brian N Finck

42. p53 orchestrates the pgc1a mediated antioxidant response upon mild redox and metabolic imbalance-Katia Aquilano

43. Skeletal muscle pgc1a modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice-Kristoffer Svensson

44. chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative and nitrosative damage to lipids and proteins-Michael Maes

45. Reexpression of pyruvate kinase m2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy-Zhihua Gao

46. Burn induced muscle metabolic derangements dysfunction are associated with activation of HIF-1a mTORC1. role of protein farnesyltaion-Harumasa Nakazawa

47. A pkm2 signature in the failing heart-Meredith L Rees

48. HIF-1a mediates a switch in pyruvate kinase isoforms after myocardial infarction-Allison Lesher Williams

49. Hyperactivity of the transcription factor nrf2 causes metabolic reprogramming in mouse esophagus-Junsheng Fu

50. The emerging role of p53 in exercise metabolism-Johnathan D Bartlett

51. pharmacological activation of ampk and glucose uptake in cultured human skeletal muscle cells from patients with me/cfs-Audrey E Brown

OXIDATIVE STRESS

Oxidative stress has been found in cancer and cfs skeletal muscle. (reference 25., 16.) Nuclear factor erythroid 2-related factor2 (Nrf2) the master regulator of the antioxidant response is activated by oxidative stress (ROS). (reference 34.) Nrf2 increases the expression of enzymes involved in glucose metabolism , pentose phosphate phosphate pathway, glutamine metabolism, glutathione metabolism and fatty acid synthesis. (reference 34.)

GLUCOSE METABOLISM

Nrf2 increase the expression of glucose transporter (glut1), hexokinase (hk), phosphofructokinase 2 (pfk2), and pyruvate kinase m2 (pkm2) . (reference 34., 49.). Glut1 transports glucose. HK converts glucose to glucose 6 phosphate (g6p). Pfk2 forms fructose 2,6 bisphosphate f-2,6-p).Pkm2 converts phosphoenolpyruvate ( pep) to pyruvate. Normally skeletal muscle express high levels of pyruvate kinase m1 (pkm1). Pkm1 converts pep to pyruvate. Pkm1 has high activity. Normally pkm2 is only expressed during the embryonic stage of life. Pkm1 is expressed in differentiated tissue such as skeletal muscle. Pkm2 has three activity modes monomeric, dimeric, and tetrameric. Pkm2 is allosterically activated. Monomeric and dimeric pkm2 can translocate to the cell nucleus to affect gene transcription. Pkm2 increases the expression of glut1, lactate dehydrogenase a (ldha) , hexokinase 1 (hk1), and pyruvate dehydrogenase kinase 1 (pdk1). (reference 35.) Ldha converts pyruvate to lactate. Pyruvate dehydrogenase kinase 1 inhibits pyruvate dehydrogenase complex (pdc).

Pentose Phosphate Pathway

Nrf2 and pkm2 both increase the expression of glut1. Nrf2 increases expression of pentose phosphate pathway (ppp) enzymes glucose-6-phosphate dehydrogenase (g6pd) and 6-phosphogluconate dehydrogenase (gpd). (reference 34.) Pkm2 being allosterically activated allows for the increased glucose 6 phosphate (g6p) to be diverted into the ppp. this results in a higher production of nadph.

Nrf2 also increases the expression of transaldolase (taldo), transketolase (tkt), and phosphoribosyl pyrophosphate amidotransferase (ppat), which leads to increased levels of phosphoribosylamine (5-pra) which is used for nucleotide synthesis. (reference 34.)

Pkm2 translocation to the cell nucleus can bind and inhibit the transcription activity of p53 . Pkm2 can also inhibit expression of p53. (reference 36.) p53 increases TIGAR activity. TIGAR lowers the level of (f-2,6-p) . F-2,6-p is a potent allosteric activator of pfk1. Pfk1 is an important enzyme in glycolysis. Pkm2 decreasing p53 activity results in lower TIGAR activity, leading to increased levels of (f-2,6-p) resulting in increased activation of pfk1. This leads to increased glycolysis.

Overall the increased nrf2 and pkm2 expression and the decreased p53 activity caused by pkm2 leads to increased expression of glut1 (increasing glucose uptake), increased expression of hk (increasing levels of (g6p)), and increased levels of (f-2,6-p). The increased f-2,6-p levels increases the activity of pfk1, this leads to increased pep being converted by pkm2 to pyruvate and then converted to lactate by the increased levels of ldha. So the increased nrf2, pkm2 and the decreased activity of p53 results in increased glycolysis and lactate levels . Increased glycolysis has been found in both cancer and cfs skeletal muscle. (reference 23., 24.) High levels of lactate has also been found in cancer and cfs. (reference 2.,3.)

Lactate Excretion

p53 induces pgc1a.(reference 42, 50.) Pgc1a induces expression of monocarboxylate transporter1(mct1). (reference 37) Mct1 transports lactate. So the increased expression of pkm2 leading to decreased p53 activity leads to decreased pgc1a, results in decreased mct1 expression and impaired lactate transport in and out of the cfs skeletal muscle cells. Impaired lactate excretion has been found in cfs. (reference 3.) This may be due to decrease mct1 expression caused by decreased pgc1a. Impaired lactate excretion can result in high levels of intracellular lactate. High levels of intracellular lactate can impair mitochondrial function.

2,3 dpg

There is increased expression of glut1 causing increasing increased glucose uptake and the increased activity of glycolytic enzymes and the expression of pkm2 (pkm2 being allosterically activated) allows for the build up of 2,3dpg. 2,3dpg is released from skeletal muscle into the blood stream is taken up by mononuclear cells. 2,3dpg inhibits the enzymes hk1, pfk1, and glyceraldehyde 3 phosphate dehydrogenase (gapd). This results in reduced energy production through glycolysis and decreased pyruvate production so less pyruvate is available for oxidation in the mitochondria affecting mitochondrial energy production also.

2.3dpg in the blood stream is taken up by red blood cells. 2,3dpg inhibits hk1, pfk1 and gapd. This result decreased production of nadph and the inhibition of the glycolytic enzymes decreases atp production. The atp levels leads to decreased glutathione levels in red blood cells because atp is required for glutathione synthesis. High 2,3dpg levels have been found in cfs and cancer.reference 17.,18.

The high 2,3dpg in the blood stream is also taken up by the liver. 2,3dpg also inhibits the glycolytic enzymes hk1, gapd, and pfk1.

Lactate and Alanine

The increased glycolysis and the increased expression of alanine transaminase and lactate dehydrogenase a results in increased lactate and alanine. (reference 34.,35.) Increased lactate release has been shown in cancer and cfs.reference 9.,3. Tumors have also been shown release alanine. (reference 9.) Maybe there is also increased of alanine release by cfs skeletal muscle. The alanine and lactate is taken up by the liver and used for gluconeogenesis . Cancer patients have increased gluconeogenesis from alanine. (reference 10.) The same increased use of alanine for gluconeogenesis maybe happening in cfs causing the low levels of alanine found in cfs patients. (reference 8.)

p53

In normal skeletal muscle cells, decreased p53 activity leads to decreased energy production from oxidative phosphorylation, but this is partially compensated for by increased glycolysis for energy production. Normal cells express pkm1 which is constitutively active so therefore has a high enough activity for increased rates of glycolysis that can partially compensate for the reduced oxidative phosphorylation. But the cfs skeletal muscle express increased levels of pkm2. Pkm2 is allosterically activated by fructose 1,6-bisphosphate (fbp). When fbp levels are low pkm2 is not activated so the level of fbp builds up. When fbp levels builds up high enough pkm2 becomes activated and atp is produced through glycolysis. The glycolysis then reduces fbp levels and pkm2 becomes inactive again. This level of glycolysis isn't enough to compensate for the reduced oxidative phosphorylation. Also increased pkm2 expression decreasing p53 activity, leading to decreased pgc1a, leads to decreased expression of monocarboxylate transporter 1 (mct1). (reference 37.) This can result in impaired lactate release and the lactate build up in the cell can impair impair the conversion of nadh to nad by the reaction of ldha. This may not allow the highest rates of glycolysis. So normal skeletal muscle cells not expressing pkm2 but expressing high levels pkm1 can better compensate for the reduced oxidative phosphorylation than cfs skeletal muscle cells expressing pkm2 .

Pkm2 can bind and inhibit p53. p53 induces sco2 gene, Sco2 is important for synthesis of cytochrome c oxidase subunit ii. the cytochrome c oxidase subunit ii is part of complex IV of the electron transport chain. So the increased pkm2 causing decreased p53 activity can results in impaired complex IV function and less effective oxidative phosphorylation.

p53 antagonizes nf-kb . High nf-kb has been found in cancer and cfs. (reference 19.,20.) The increased pkm2 decreasing p53 activity takes away the antagonist of nf-kb, allowing higher nf-kb.

Pyruvate Metabolism

Pkm2 increases expression of pyruvate dehydrogenase kinase 1 (pdk1). Pdk1 inhibits pyruvate dehdydrogenase complex (pdc). (reference 35.) The decrease p53 activity increases the levels of pyruvate dehydrogenase kinase 2 (pdk2) and phosphorylated pyruvate dehydrogenase (p-pdc). Pdk2 inhibits (pdc) . Increased levels pdk1, pdk2 and p-pdc leads lower activity of pdc and less conversion of pyruvate to acetyl coa. (reference 38.) So overall the increased pkm2 expression leading to increased pdk1, and the decreased p53 activity leads to higher levels of pdk2 and p-pdc leads to less pyruvate being coverted to acetyl coa because of the lowered activity of pdc. So there is less acetyl-coa to fuel the tricarboxylic cycle (tca) cycle to produce nadh which is used to fuel the electron transport chain for oxidative phosphorylation.

Glutamine metabolism

Increased nrf2 activity increase enzymes SLC1A5 glutamine transporter, GLS glutaminase converts glutamine to glutamate and ALT alanine transaminase converts pyruvate and glutamate to alanine and alpha-ketoglutarate. Nrf2 also increase enzymes involved in glutathione synthesis SLC7A11 cysteine transporter, GCLM, GCLC and GSS glutathione synthetase. There is increased glutamine uptake and increased conversion to glutamate providing substrate for glutathione synthesis. The increased glutamate and the increased enzymes of glutathione synthesis results in increased glutathione levels. Increased levels of glutathione has been found in cfs skeletal muscle and cancer. (reference 16., 14.)

The increased glutamine metabolism also provides glutamate that enters the tca cycle as alpha-ketoglutartate. The alpha-ketoglutatrate flows through the tca cycle and forms oxaloacetate that is converted to aspartate by asparrtae transaminase (AST). Aspartate produced by the tca cycle is used by cancer cells for anabolic pathways. (reference 7.) High glutamine and glutamate metabolism results in high alpha-ketoglutarate levels. High apha-ketoglutarate levels have been found in cfs. (reference 39.) The high alpha-ketoglutarate found in the cfs patients plasma may have been released from the cfs skeletal muscle. In cfs skeletal muscle the flow of alpha-ketoglutarate through the tca cycle forms oxaloacetate which is converted to oxaloacetate, which is converted to aspartate by ast. results in a build up of aspartate . High aspartate has been found in cfs. (reference 6.) Perhaps the high aspartate found in cfs patients results from the high aspartate released from skeletal muscle. Cancer cells use aspartate for cell proliferation but the cfs skeletal does does not use aspartate for cell proliferation so this results in a build up of aspartate in the cfs skeletal muscle. The reason for the increased flow of oxaloacetate being converted to aspartate is because pyruvate dehydrogenase is inhibited by increased pdk1, pdk2 and p-pdc.

The increased use of glutamine for glutathione synthesis, and increased glutamate , alpha-ketoglutarate flow through the tca cycle may explain the decreased glutamine levels found in cfs skeletal muscle and cancer.(12.,13.)

Fatty Acid Metabolism

p53 induces expression of carnitine palmitoyltransferase I (cpt1). Cpt1 transports activated fatty acids into the mitochondria. p53 induces lipin1. (reference 40.) Lipin1 induces expression ppra.(reference 41) p53 induces pgc1a expression.(reference 42., 50.) The ppar/pgc1a axis induce expression cpt1. p53 induces expression of cd36 fatty acid transporter. So the increased expression of pkm2 causing decrease p53 activity decreases pg1a leading to decreased cpt1 and cd36. This results decreased fatty acid uptake into the cfs skeletal muscle cells and decreased transport of activated fatty acids into the mitochondria . So there is decreased fatty acid oxidation in cfs skeletal muscle.

Ketone uptake and ketolysis

p53 induces expression of pgc1a.(reference 42., 50) Pgc1a induces expression of enzymes involved in ketone uptake and ketolysis Mct1, 3 hydroxybutyrate dehydrogenase type1 (Bdh1), 3 ketoacid coenzyme A transferase 1 (Oxct1), and acetyl coa acetyl transferase (Acat1). ( reference 43.) So the increased in pkm2 leading to p53 activity leads to decrease pgc1a expression. Decreased pgc1a expression leads to decreased expression of enzymes involved in ketone uptake and ketolysis. So the cfs skeletal muscle cell is less able to utilize ketones for energy production.

Altered Energy Production Pathways

The increased oxidative stress induces nrf2, increases pkm2 expression. Pkm2 decreases p53 activity. Decreased p53 activity decreases pgc1a. There is increased expression of glucose uptake enzymes (glut1) and glycolysis enzymes (pfk2) and (hk). There is decreased expression of enzymes required for fatty acid uptake cd36 , and decreased expression of enzymes for fatty acid transport into mitochondria cpt1. There is decreased pyruvate dehydrogenase activity caused by increased levels of pdk1,pdk2 and p-pdc. There is decreased expression of enzymes required for uptake of ketones and ketolysis mct1, bdh1, oxct1, and acat1 . There is increased expression of enzymes involved in glutamine uptake and increased expression of glutaminase enzyme. There is increased glutamine flow through the tca cycle as alpha-ketoglutarate. So overall there increased glutamine usage and increased glycolysis. There is also reduced pyruvate oxidation, fatty acid oxidation, and ketone oxidation in the cfs skeletal muscle cell.

Pgc1a also induce expression of tca cycle enzymes citrate synthase (cs), aconitase (aco2), and isocitrate dehydrogenase(idh3a). So increased pkm2 expression,leading decreased p53 activity, leads to decreased pgc1a, which leads decreased expression of cs, aco2, and idh3a.(reference 43.)

Pgc1a also induces genes involved in mitochondrial oxidative phosphorylation (uqcrc2, sdhb, and ndufb8) . Uqcrc2, sdhb and ndufb8 are genes involved in the formation of electron transport chain complexes I, II, and III .

Increased activity of nrf2 increases pkm2 expression. (reference 49.)

Overexpression of pkm2 has been shown to decrease p53 and this resulted in decreased atp and severe mitochondrial dysfunction. (reference 36.)

Reexpression of pkm2 has been observed in type 1 muscle fibers of patients with myotonic dystrophy type 1.-(reference 45.)

Increased expression of pkm2 in skeletal muscle has been found after burn injury. Increased expression of pkm2 has been found in the hearts of humans with heart failure. Increased expression of pkm2 has been found in hearts after myocardial infarction. (reference 46., 47., 48.) These indicate increased pkm2 expression results to deal with trauma or stressors possibly, as well as oxidative stress.

Ampk activity

Ampk activity has been found down-regulated in cancer and cfs. (reference 30., 31. 51.) In cancer the reduction in ampk activity correlates with cancer progression. There are many factors that contribute to the down-regulation of ampk activity in cancer. (reference 30.) Electrical pulse stimulation (eps) in cultured myotubes from cfs patients failed to show ampk activation. (reference 31.) Pharmacological activation of ampk with metformin and compound 991 (activator of ampk) increased ampk activity in cfs myotubes. Metformin and compound 991 also increased glucose uptake in cfs myotubes. Metformin and compound 991 failed to affect the decreased atp levels found in cfs muscle cells. (reference 51.) This suggest that there are multiple factors keeping ampk activity down-regulated. Electrical pulse stimulation (simulating exercise) and pharmacological failed to affect the decreased atp levels in cfs cultured myotubes. (reference 31., 51.) This indicates that other than ampk, other energy producing pathways are also down-regulated in the cfs muscle cells and that simple pharmacological activation of ampk will not increase the atp level in cfs muscle cell.

So how did we get here, what keeps us in the cfs state?

Oxidative has been shown to initiate some forms of cancer. Oxidative stress has been found in cfs skeletal muscle cells. Oxidative stress may have initiated cfs. cancer cells require a certain amount of oxidative stress (ROS) to push cell proliferation. Due to the increased ROS cancer cells have an upregulated antioxidant defenses. This upregulated antioxidant defense allows for an increase of a required amount of ROS but quenches extra ROS that can be damaging to the cancer cell. Cancer cells have also made changes that allows them to tolerate a higher level of ROS than normal cells. To keep a higher level of ROS cancer cells have altered there metabolism and made changes to the activity of certain enzymes. So the cancer cells have adopted a mechanism that keeps them in a cycle of increased oxidative stress (ROS), increased antioxidant defense and altered energy metabolism and other changes to certain enzymes . Since oxidative has been shown in cfs skeletal muscle cell. Since oxidative stress has been shown to initiate some forms of cancer and oxidative stress may have initiated cfs, and increased oxidative stress, upregulated antioxidant defenses and an altered energy metabolism has been shown in cfs skeletal muscle, cfs skeletal may have adopted the same mechanism that occurs in cancer cells, that keeps the cancer cells in a cycle of increased ROS, upregulated antioxidant defenses and altered energy metabolism/and other changes to certain enzymes, so this mechanism keeps the cfs skeletal muscle cell in a cycle of increased ROS, upregulated antioxidant defenses and altered energy metabolism/changes to other enzymes and this keeps us in the cfs state. I believe this mechanism takes place in all animals as a defense mechanism against oxidative stress and the system down-regulates itself once the threat is gone, but in cfs the system might have been altered so much that we get stuck in this cycle, the same way that cancer cells are stuck in this cycle.

Immune/Inflammation

A word about immune. Oxidative stress and lipid peroxidation has been shown in cfs skeletal muscle.(reference 16.) Lipid peroxidation products causes the activation of the immune and inflammation. Treating inflammation directly may offer some relief but will not fix the energy problem occurring in the muscle. Rebalancing the altered pathways in the muscles takes care of the energy issues and lipid peroxidation then the immune problem wouldn't occur. (reference 44.) chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative and nitrosative damage to lipids and proteins-Michael Maes
 
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sb4

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@phillybadboy Very good, I think you have hit on the pathways of what is happening in at least some of us, regarding energy metabolism. The question I have had is why don't CFS get cancer at significantly higher rates. I have read a study that said cancer is more likely to occur sooner in CFS but still, I would have thought drastically sooner.

You read Prustys recent (half a year ago) paper? If I had to guess I would say that a "stealth" pathogen is causing our bodies to react in the ways you lay out. The pathogen causes the body to go in defense mode and upregulate oxidative stress etc in order to eliminate the pathogen but the pathogen escapes this somehow, leaving us in this constant, defensive, high glycolysis state.

Do you notice a significant worsening of symptoms upon carb ingestion that lasts roughly the amount of time it takes for your blood sugar to return to baseline (couple of hours)? I have this symptom and I think it is thanks to lowered PDH and the other mechanisms you lay out in your OP.
 

Methyl90

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I'm a bit tired but I try to answer:

What happens if i inhibit PKM2? I hope not to get confused but I BELIEVE that T3 / T4 have an impact on inhibition along with insulin, glucagon, alanine.

I have done numerous experiments to increase lactate by reading many articles by Doris Loh.

Through the ascorbic acid I have noticed big cognitive improvements but at the same time a strong migraine ... so either I struggle to dispose of it or the excess nitric oxide causes me migraines and slowed mitochondrial breathing.

However, I can confirm that if USED BY THE BODY correctly, lactate is superior to glucose and ketones.

I have always had low blood levels of both lactate and pyruvate (fasting) including low insulin level (fasting) and poor response after carbohydrate and protein meals which should raise it.

I would not call it insulin resistance, but a totally absent response from the pancreas for as yet unknown causes.

No insulin = non-functioning pyruvate dehydrogenase.

ALA S (ONLY S and not R) mimics insulin, at least on me and you can feel the difference.

Calcium Pyruvate 500-1gr per day is what really makes me live normally.

Finally, I SPEAK FOR MYSELF AND ACCORDING TO THE EXPERIENCE OF SYMPTOMS ... my glycolysis and consequent production of pyruvate / lactate is poor.

It escapes many that the final product of glycolysis is actually LACTATE, not pyruvate ... if there is no pyruvate there is no conversion to lactate.

ONLY AFTER, if you want to limit lactate it's very simple.

I am aware that everyone is different but at the moment a normal insulin release and a higher pyruvate level are making a huge difference along with stress control through spinal movements dictated by a chiropractor.

I forgot: the FAO and HDAC inhibitor vitamin E helps a lot with the recovery of lost muscle mass, not like steroids but it helps.

Work on mobility and proper alignment with a chiropractor or physical therapist.
 
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sb4 I wasn't suggesting you can get cancer sooner or later, I am suggesting that this is a common mechanism in response to the threat, but it also affects your energy producing pathways. I believe that this mechanism to protect against oxidative stress, happens in all animals and once the threat is gone the mechanism down-regulates itself, but in cfs you get stuck in this cycle the same way cancer is stuck. I have some ideas to down-regulate or rebalance this cycle and hopefully normalize the energy pathways.
 

sb4

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@phillybadboy Ok that makes sense. I think the current theory on cancer is genetic mutations precede the Warburg metabolism however there is a competing theory that the Warburg metabolism causes the mutations. If theory 2 is correct then we should be getting more cancer. Although I concede that I don't understand this stuff well at all.
I have some ideas to down-regulate or rebalance this cycle and hopefully normalize the energy pathways.
I am very interested in these ideas.

You think the cfs cell is stuck in a cycle as opposed to the pathogen still existing in the background? It could be either I suppose.
 
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Methyl you're getting it a little bit, In healthy people, pkm1 which is normally found in skeletal muscle is always highly active so produces lots of pyruvate but you don't see a lot of lactate build up because pyruvate dehydrogenase is fully active and so is oxidative phosphorylation.

In cfs pkm2 expression is upregulated, pkm2 is allosterically activated so its not always active. pkm2 is only active when its allosteric agonist (fructose 1,6 bisphosphate) is high enough. If fructose 1,6 bisphosphate is high enough then you see higher lactate, you see higher lactate because lactate dehydrogenase (lactate) is also upregulated and pyruvate dehydrogenase is inhibited. So sometimes you see high lactate when pkm2 is activated and low lactate when pkm2 is not activated. Even when pkm2 is active you may not see higher pyruvate because other pathways that metabolize pyruvate such as lactate dehydrogenase and alanine transaminase are also upregulated in cfs muscle.

Pkm2 can affect gene transcription, and inhibit p53. p53 itself is involved in the transcription of many genes that affect energy production. p53 affects the transcription of genes in pyruvate dehydrogenase, fatty acid oxidation, ketone oxidation, citric acid cycle eznymes and electron transport chain enzymes.

You don't try inhibit pkm2 activity per say as in inhibiting the conversion of pep to pyruvate. You try to inhibit the nuclear translocation of pkm2, because this is where it can affect gene transcription that can result in altering the energy production pathways.

I have seen some studies that shows what happens when you inhibit the translocation of pkm2 to the cell nucleus. i'll post them later.

I have a treatment in mind, it affects, inhibits the nuclear translocation of pkm2.
 
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sb4 cancer can be caused by genetic mutations or oxidative can cause the genetic mutations. But the mechanism that I speak of in cfs isn't caused by genetic mutations its just a downregulation or upregulation of certain enzymes. Whatever the original trigger for initiating cfs is already long gone. What is left is the cycle used to protect against the oxidative stress threat by that original trigger. Yes cfs people have the Warburg effect when pkm2 is active that's why you see high lactate. but pkm2 is not always active that's why sometimes you see low lactate. This is because pkm2 needs to be allosterically activated, unlike pkm1 which is always active.

I have a treatment mind to try to modulate the pkm2 nuclear translocation which is where it affects transcription of genes the alter energy production pathways.

In cfs the upregulated immune/inflammation that we see is actually the result of whats happening in the muscles. The oxidative stress in the muscles causes lipid peroxidation of the cell membranes in the muscles, the immune system reacts to the lipid peroxidation products. Treating inflammation may give you some relief but will not fix your energy production. The way to fix energy production is to rebalance whats happening in the muscles. I don't believe cfs is an autoimmune disease if it was, you could treat it the same way you treat any other immune diseases. Although there is immune irregularities in cfs, this is only the result of oxidative stress and lipid peroxidation in skeletal muscle.
 
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Wishful

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A complex hypothesis, and it may fit observations from some PWME, but it doesn't fit those of us for whom ME hasn't affected our muscle performance. From my observations, ME is a neuroimmunological disease.
 
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Wishful, I actually believe this mechanism is also happening in the brain. I believe this mechanism is only happening in muscle and brain, because these are highly energetic organs with the potential to generate a lot of oxidative stress, So would require up-regulation of pkm2 to upregulate the antioxidant system (and kick-start this mechanism , this cycle.

I thougth all cfs/me patients have lack of stamina in their brain and muscle ( the lack of muscle stamina and brain fog is my main two symptoms). I also have upregulated immune signs, and symptoms of inflammation.

I believe the immune/inflammatory response only downstream to what is happening in the muscle, the lipid peroxidation of muscle membranes due to oxidative stress in muscles. reference - Chronic fatigue syndrome is accompanied by an igm related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins- Michael Maes
 

Learner1

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Some people have BRCA1, ATM, Lynch syndrome, and a number of other genes predisposing then to cancer. Many of these affect the ability to repair DNA.

For most others, cancer is a metabolic disease.

https://www.amazon.com/dp/1603587292/ref=cm_sw_r_cp_apa_fabt1_W.CXFb7323S4R

https://www.amazon.com/dp/0470584920/ref=cm_sw_r_cp_apa_fabt1_VcDXFbFJCA170


There are a few of us who have had both cancer and ME/CFS, not a lot. So I'd be hesitant to make any across the board correlations between the two.

But, I'd caution you that cancer is not one amorphous blob, but over 200 different diseases of mutated cells, all with damaged mitochondria, and especially blood and solid cancers are very different.

Several of us do not have high lactate - many do, many times related to thiamine deficiency. Mine is usually below range, along with my pyruvate, on multiple tests, and I've seen the same in other PwME labs.

As for alanine, there are several reasons for low alanine, including gut malabsorption and protein deficiency or malabsorption, which is quite common in PwME.
Screenshot_20201201-001934.png


Most of us do have various issues with energy production. Researchers have found quite a variety of situations in various groups of patients and explanations. There is no consistent explanation. The same with cancer patients.

Oxidative and nitrosative stress are contributors in both as you mention. But the causes can be different. Two markers that are useful to watch are 8OH-dG and lipid peroxides, markers of DNA damage and cell membrane damage respectively. But, there is no consensus as to exactly where they come from or how to counteract them. Martin Paul's protocol can do a lot to cut back on nitrosative stress, but the oxidative stress can come from a number of different places, and not every one is easily found or addressed.

The thing that concerns me about seeing even well gathered lists like yours @phillybadboy is that there's a tendency to blame the patient or at least tell them they're stupid for not figuring it out and doing something about it and that's why they're sick. The human body is tremendously complex, the interplay of genes and epigenetics and infections and toxins and what the mitochondria are doing create an incredible number of permutations of what could be going wrong at any given moment, and though a lot can be done to help, it is not possible to counteract all of things you've listed, nor maybe is it not the best idea to try in some cases.

I coincidentally spent part if today at one of the top cancer centers in the world, discussing my concerns about some of the things you've listed and asked ng for more help, but it's clear, as I've found before with other cancer experts that investigations and reducing risks from the things you've listed is not something they usually think about.Nor gave my conversations with the National Cancer Institute been productive. They offered me art and acupuncture, and when I pushed and said while they're both nice, they don't begin to touch the depth and seriousness of the problems I've seen, they came back with the same article my doctors and I have been using as a guide to help me, see attached...

It's been discussed elsewhere on this site, but my dream is to live in a time of a Star trek style tricorder but a doctor could wave over a patient and make us all better.

But, thank you for your work and gathering these things, and bringing this to our attention. It's always worth reviewing stuff like this even though it may not be true for all of us. For someone it might be just the revelation that's needed....

At the worst of my cancer, I found the book, Anticancer, to be quite uplifting.

https://www.amazon.com/dp/0452295726/ref=cm_sw_r_cp_apa_fabt1_0uDXFb25JK0KA
 

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@phillybadboy Very good, I think you have hit on the pathways of what is happening in at least some of us, regarding energy metabolism. The question I have had is why don't CFS get cancer at significantly higher rates. I have read a study that said cancer is more likely to occur sooner in CFS but still, I would have thought drastically sooner.

You read Prustys recent (half a year ago) paper? If I had to guess I would say that a "stealth" pathogen is causing our bodies to react in the ways you lay out. The pathogen causes the body to go in defense mode and upregulate oxidative stress etc in order to eliminate the pathogen but the pathogen escapes this somehow, leaving us in this constant, defensive, high glycolysis state.

Do you notice a significant worsening of symptoms upon carb ingestion that lasts roughly the amount of time it takes for your blood sugar to return to baseline (couple of hours)? I have this symptom and I think it is thanks to lowered PDH and the other mechanisms you lay out in your OP.
it really depends for me- sometimes a huge carby meal makes me feel better. IF I’ve been eating carbs, if I’ve been fasting/low carb and then eat carbs I will get exhausted
 

gbells

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The mechanism is that when ME patients exercise they have a nonfunctional Citric Acid cycle because mitochrondria are inhibited by viruses so they can only burn glucose through glycolysis, not fat as healthy people can. This causes the lactic acid build up.

The glycolytic process requires that muscle cells breakdown glycogen to glucose via the glycogen phosphorylase pathway2. However, in high intensity anaerobic exercise, the body initially uses up all of the glycogen in the skeletal muscle and the liver through the glycolysis pathway, creating buildup of lactic acid.
http://umich.edu/~medfit/resistance...requires that,creating buildup of lactic acid.
 

Methyl90

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The mechanism is that when ME patients exercise they have a nonfunctional Citric Acid cycle because mitochrondria are inhibited by viruses so they can only burn glucose through glycolysis, not fat as healthy people can. This causes the lactic acid build up.


http://umich.edu/~medfit/resistancetraining/timingiseverything101705.html#:~:text=The glycolytic process requires that,creating buildup of lactic acid.

What do you think about Mildronate which inhibits FAO by blocking carnitine synthesis? could promote the absorption of glucose in the mitochondrion?
 

gbells

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What do you think about Mildronate which inhibits FAO by blocking carnitine synthesis? could promote the absorption of glucose in the mitochondrion?
My guess is it probably won't work. Antidotes have to be very specific to target the molecular pathway to work. Although I'm not sure if scientists have figured out exactly how the mitochrondria are being ihhibited yet. I just use d-ribose and nicotinamide riboside to work around it and spoon out my energy which is about 45% normal currently (ME contracted 2008). Energy demands are pretty high with the immunotherapy regimen still going.