Fibromyalgia, Endoplasmic Reticulum Stress, Neurotoxicity and CAMKII

Many experts now believe pain sensitivity in fibromyalgia is in part, neuropathic pain. "Martinez-Lavin notes that neuropathic pain is stimuli-independent and is accompanied by allodynia and paresthesia, which are also common features of fibromyalgia. He also points out that the most important characteristic of neuropathic pain is not the nerve lesion, but the resulting nerve dysfunction." (Kelly) Nociceptors (ie. TRPV1) can be upregulated in neuropathic conditions in addition to other inflammatory pain disorders. Also, a number of different agents activate nociceptors including those in food, fragrances and chemicals and other noxious stimuli like heat, cold and pH. Hormonals and neurochemical signals such as IGF and H2O2 and cytokines such as MCP-1 can increase the sensitivity of nociceptors which reduce their threshold for activation.
Upon activation of TRP channels, there is a flood of calcium inside the cell. Consistent and long-term activation and subsequent intracellular exposure to increased calcium may result in endoplasmic reticulum stress. Two consequences occur from ER stress 1) the activation of Nrf2 through PERK (Ho) which in endothelium includes Ho-1 binding to Nrf2 (Liu) and the 2) activation of CAMKII which may increase levels of cytokines and increase the likelihood of neuronal damage if not prevented. In cardiac cells, the inhibition of an isoform of CAMKII protects against intracellular levels of Ca+, H2O2 and acidosis in addition to protection from mitochondrial-induced apoptosis. Generally, H2O2 is generated through several mechanisms including from the mitochondrial respiratory chain and from activation of NADPH oxidases and can increase significantly during mitochondrial dysfunction. H2O2 signaling exerts prolonged signaling effects including those on dopamine release and down-regulation of CAMKII helps to prevent dopamine neurotoxicity(Cai, Bao). The activation of CAMKII from oxidative stress as noted by Xie, is responsible for "arrhythmia in diseased hearts and the heart's response to catecholamines in the "flight-fright" response (Cai). Also, CAMKII interacts with both TRPV1 and the NMDA receptor to alter their function. As for the latter, it may inhibit the downregulation of the NMDA receptor and increase the potential for pain generation and neurotoxicity.
Citations

Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

A study that was published last year suggested that MCP-1/CCL2/CCr2 and eotaxin may be good biomarkers for fibromyalgia and identify a genetic component to the condition. (Zhang) Since then, researchers have noted that both chronic fatigue syndrome and fibromyalgia may be classified as inflammatory conditions when the exact cause of symptoms is not known. Interestingly, MCP-1 can cause inflammatory responses and therefore has the potential of contributing to sickness behavior syndrome which is a condition that results in behaviors often associated with people that are ill. Sickness behavior does not seem exclusive of human beings because similar behaviors have been observed in other animals. Maes concludes that oxidative and nitrosative stress contribute to the development of chronic fatigue which result in an increase inflammation, NF-kappaB, COX2, iNOS and damage to lipids and proteins. He further explains that triggers include strenuous exercise, LPS from gram negative bacteria, viruses and pshycological or physical stress. A few of the symtoms associated with sickness syndrome include fatigue, malaise, appetite changes, anxiety, depression, weight changes, sleep alterations and numerous others. (Maes) Previous studies show it can be stimulated by a variety of conditions including IGF-1, Tnf-a and Il-1b the latter two are produced as part of the stress response and modulated by the Nrf2 system that also stimulates induction of antioxidants. (Dantzer) Nrf2 has been shown to modulate metabolic homeostasis in adipocytes and is now linked with obesity. Nrf2 is responsible for detoxification of electrophiles and xenobiotics and the function of it can be altered by any number of environmental factors including but not limited to metals, nutrition, and other protein interactions such as the AhR which also may play a very important role in chemical sensitivity.

The severity of sickness syndrome has been demonstrated to be determined on the prevalence of the anti-inflammatory immune complex IL-10. When it is present the duration of sickness syndrome is less and the effects like memory and learning impairment are also decreased. (Richwine) Il-10 has been shown to reduce the levels of IFN-gamma and Tnf-a- induced production of superoxide and nadph oxidase 1 (NOX1) which would suggest prevention of ROS generation from it. (Kamizota) Il-10 also stimulates the induction of HO-1 and therefore may activate the Nrf2 pathway but HO-1 can act independantly. Inhibition of HO-1 significantly reduces the protective effects of Il-10 on Tnf-a by LPS. Lee et al shows that this relationship also involves carbon monoxide, a gasoneurotransmitter, on the protective effects of Il-10. Therefore this further suggests a possible involvement of Nrf2 considering that Nrf2 modulates the effects of carbon monoxide. (Lee) De Wilde demonstrated that production of Il-10 is completely abolished with inhibition of HO-1.

Nrf2 is now associated with protective effects in adipocytes. Eotaxin is a chemokine that is elevated in obesity because adipose tissue seems to be the predominant source of it. It is also an important inhibitor of MCP-1 and is a common factor in allergic reactions. Its presence at the site of allergic inflammation suggests coordinated cellular responses of allergic inflammation where both MCP-1 and eotaxin are present. (Olgilvie) Tnf-a is overexpressed in obesity (Uysal) and associated with insulin resistance and inhibition of the expression of numerous genes including PPAR-gamma and adiponectin. It is also an important inducer for prolonging the half-life of eotaxin.

Summary:

• Maes has suggested that a pathway to chronic fatigue syndrome is by LPS endotoxin and therefore because the production of Il-10 modulates the severity of sickness syndrome through HO-1. We can suggest that the alteration in signaling of Nrf2 could ultimately lead to CFS and sickness syndrome.
• Nrf2 is conserved in different organisms, the homolog in C elegans is skn-1. (An)
• Nrf2 can be ethnically derived and therefore some populations may be more susceptible to some of the triggers and have an increased risk for chronic fatigue syndrome. (Marzec, Dinos)
• EGCG has been shown to have positive effects on chronic fatigue syndrome in a mouse model of CFS. Studies have shown that EGCG increases induction of HO-1 through Nrf2.
  

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Source Citations

Mitochondrial Bioenergetics, CFS, Muscle Fatigue, PGC-1a, CAMKII and Nrf2.

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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