- Messages
- 56
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
(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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