Chronic fatigue syndrome is a condition that includes overwhelming fatigue even with rest that lasts for a period of six months or longer. It has been 3 decades since research on the condition began and there is no definitive answer on what causes it. However, they are making research strides and have an idea of at least some things that may contribute to it. SIRT1 activity regulates most of its activity through PGC-1a which an important regulator of metabolic homeotstasis, cellular function and mitochondrial biogenesis. Generally, cells that are lacking in PGC-1a are more insulin resistant and also have less eNOS.
In chronic fatigue syndrome, patients have a slow to fast twitch muscular presentation and altered muscle metabolism. (Pietrangelo) CAMKII is also important in fast-twitch muscle for sustaining contraction during exercise and it has been demonstrated that lower levels of CAMKII which are common in mitochondrial respiratory deficiencies may effect muscle performance. (Tanaka) AMPK is also another important regulator of this pathway through phosporylation of PGC-1a (Jager). AMPK also improves fatty acid metabolism in muscle and that activity is partially dependant on CAMKII (Rose). Again, a decrease in CAMKII would surely lead to changes in muscle metabolism. In this case, poor fatty acid metabolism causes higher fat in the muscle and is associated with insulin resistance and obesity and potentially, diabetes. (Adams) Interestingly, 89% of the muscles around the eyes and certain other areas of the face are fast-twitch muscles which may contribute to certain types of facial pain. Fast twitch muscle have less PGC-1a and as a result mitochondrial content is decreased and muscle activity is “energetically less efficient and expensive”(Schaffer). Cells with higher levels of PGC-1a have a better recovery of mitochondrial function to oxidant stress than those with lower levels of PGC-1a. (Rasbach) This would suggest a down-regulation or inhibition of SIRT1 activity which can be inhibited by many factors including nutrition including excessive calorie intake, Tnf-a or overproduction of H2O2. Many exposures including those to dioxin can increase levels of the pro-inflammatory Tnf-a (Frigo). Overall, cells with negative alterations in PGC-1a have demonstrated metabolic abnormalities, are more sensitive to cold, have more degenerative lesions and when expoxed to H2O2 are more apt to become damaged.
Because Nrf2 regulates NRF1 which is intricately tied and necessary for PGC-1a cellular function, Nrf2 becomes an important part of the pathway of SIRT1 and PGC-1a. Piantadosi describes the process as ”Nrf2 upregulates the mRNA, protein, and activity for HO-1 as well as mRNA and protein for nuclear respiratory factor (NRF)-1. Mechanistically, in cardiomyocytes, endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H2O2 production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3 (GSK3b), which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter.” (Piantadosi) In simple terms, GSK3b can become an on/off switch for Nrf2 and you got to have the promoter nuclear respiratory factor NRF-1 and Nrf2. In terms of mitochondrial function, it seems like the NRF-1/Nrf2 complex would be an important place where future therapies target. One already in existence that provides some of this action is metformin which is used as a diabetes treatment. Exercise may increase levels of PGC-1a but this is inhibited in insulin resistant muscle.(Filippis) Resveratrol and quercetin may improve mitochondrial function.
Notes:
****Nrf2 SNPS can be ethnically-derived which would make people with more (or less) susceptible to oxidative stress and possibly a decrease in mitochondrial biogenesis. (Marzec)
****SNPs or mutations may make Nrf2 less responsive or overly responsive to cell signals.
****Friedrich's Ataxia is a condition caused by an alteration in coding for Nrf2 which leads to poor induction of the antioxidant system. It is not the only form of ataxia. Read more about ataxia here. Other SNPs may cause one to be more sensitive to lung injury. Some of the symptoms may seem similar to those with some symptoms related to chemical sensitivity.
****The Nrf2 regulates a number of proteins including the aryl hydrocarbon which may be an important initiator and factor in multiple chemical sensitivity. The AhR is responsible for mediating the detoxification of PAHs and HAHs in addition to other xenobiotics. It has also been determined it mediates most of the toxicity associated with dioxins.
This is a list of common symptoms associated with CFS:
*cognitive dysfunction, including impaired memory or concentration
*postexertional malaise lasting more than 24 hours (exhaustion and increased symptoms) following physical or mental exercise
*unrefreshing sleep
*joint pain (without redness or swelling)
*persistent muscle pain
*headaches of a new type or severity
*tender cervical or axillary lymph nodes
*sore throat
Other Common Conditions:
*irritable bowel, abdominal pain, nausea, diarrhea or bloating
*chills and night sweats
*brain fog
*chest pain
*shortness of breath
*chronic cough
*visual disturbances (blurring, sensitivity to light, eye pain or dry eyes)
*allergies or sensitivities to foods, alcohol, odors, chemicals, medications or noise
*difficulty maintaining upright position (orthostatic instability, irregular heartbeat, dizziness, balance problems or fainting)
*psychological problems (depression, irritability, mood swings, anxiety, panic attacks)
*jaw pain
*weight loss or gain
Source: CDC
Citations: Original Post Source
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