Could muscle inflammation contribute to the pain and stiffness of fibromyalgia?
Science: Elevated NF-kB activation was observed in the muscle of those with fibromyalgia, along with inflammatory cells and elevated pro-inflammatory cytokines.
Conclusion: An inflammatory mechanism appears to at work and might at least partly explain muscle pain and stiffness.
RAGE mediated activation of NF-kB may explain the origin and perpetuation of muscle pain and muscle stiffness in fibromyalgia.
This is an important publication because it:
- Demonstrates excess activation of NF-kB (hence inflammation) in and around the muscles of fibromyalgia patients;
- Provides a possible explanation for connective tissue changes in fibromyalgia, such changes possibly resulting in or exacerbating pain; and,
- Suggests one means by which local pain and inflammation might become self-perpetuating, and perhaps spreading, in fibromyalgia.
AGE and RAGE
AGEs are Advanced Glycation Endproducts.
Under certain conditions, sugars can bind with proteins or fats to create an Advanced Glycation Endproduct – an “AGE“. The reaction by which the AGE is formed can take place in food before it is eaten. Or that reaction can occur inside the body after sugar is consumed.
Fructose is believed to form AGEs 10x more easily than glucose. So consuming a lot of high fructose corn syrup (e.g. as in soda) might not be a good thing – because AGEs are bad for us.
AGEs have the ability to link up with (attach to) other AGEs, so when they are present in sufficient concentration in a tissue they can all link together – resulting in a ‘stiffer’ and less functional tissue.
AGEs are also bad because they cause inflammation – by binding to a specific receptor on the cell surface. In fact it is likely that this is the major reason AGEs are bad – because they cause inflammation – perhaps only local inflammation, or only inflammation at the cellular level – but inflammation nonetheless – which may result in pain.
A large body of evidence suggests that AGEs are an important cause of almost all diabetes complications. Diabetics have much higher levels of AGEs because excess blood sugar results in an excess AGE production. That’s one of the major reasons why it’s important for diabetics to keep their blood sugar under control. AGE production in diabetics may be associated with neuropathic pain.
Besides diabetes, other chronic, inflammatory conditions that have been linked to RAGE include atherosclerosis, congestive heart failure and Alzheimer’s disease.
RAGE is the Receptor for Advanced Glycation Endproducts.
Once the AGE is formed, is has the ability to bind to a cell via the Receptor for AGE – “RAGE“. The result of AGE binding to RAGE is the activation of NF-kB. NF-kB acts very much like an inflammation ‘master switch’. Its activation ‘turns on’ inflammation. So activation of NF-kB by RAGE results in, or at least strongly suggests, inflammation.
What’s worse, activation of NF-kB also results in the production of more receptors – more RAGE.
So a self-perpetuating, vicious cycle can emerge. AGE binds to RAGE which results in more (excess) NF-kB activation, leading to inflammation, AND resulting in the production of yet more RAGE. The additional RAGE can then (again) bind to more AGE leading to more NF-kB activation, more inflammation and more RAGE (etc.) The cycle can, in theory, repeat indefinitely – or at least until there is no more AGE to bind.
Of course this is very bad, and it is easy to see how it might lead to localized ‘hot spots’ of inflammation – and pain (because inflammation causes pain.)
RAGE and AGE in fibromyalgia
RAGE has not previously been considered to play a significant role in fibromyalgia, but the study summarized below suggests that it might be important.
Significantly higher levels of AGE were found in the blood of those with fibromyalgia compared to those who did not have fibromyalgia.
Differences in the muscles of those with fibromyalgia were also observed:
As an expected result, greater activation of NF-kB was observed in the muscle of those with fibromyalgia.
And, as expected when NF-kB is activated – more inflammatory cells were seen in the muscle of those with fibromyalgia.
Finally, RAGE could not be observed in the tissue of those without fibromyalgia. But in those with fibromyalgia RAGE receptors were present in sufficient concentration to be observed (by the staining methods employed.)
As noted above, by activating NF-kB, RAGE can initiate a vicious cycle of localized inflammation. And, indeed, this is exactly what was observed – both excess activation of NF-kB, RAGE, and inflammatory cells – only in those patients with fibromyalgia.
The authors conclude by suggesting that AGEs found in excess in the muscle of fibromyalgia patients may impact the disease:
- By affecting collagen structure – thus affecting connective tissue changes; and,
- By activating NF-kB – thus resulting in self-sustaining, and ultimately spreading, pain and inflammation.
An explanation for the stiffness of fibromyalgia?
Stiffness is one of the most prominent symptoms of fibromyalgia, yet there is essentially no explanation for this stiffness.
One thing we know is that stiffness does not originate in the central nervous system. It cannot be explained by central sensitization. Whatever it is, the cause of stiffness must be within the muscles and joints themselves.
The inflammatory process described here, including the production of pro-inflammatory cytokines within the muscle, seems to offer the best possible explanation for the stiffness of fibromyalgia.
Please see further discussion and conclusions following the article excerpt below.
Detection of elevated N epsilon-carboxymethyllysine levels in muscular tissue and in serum of patients with fibromyalgia.
Summary of the abstract
OBJECTIVES: To compare levels of CML, an AGE (advanced glycation end product) present in the muscle tissue and in the serum of patients with fibromyalgia (FM) vs. healthy controls.
METHODS: The serum levels of CML were measured in 41 patients with FM and 81 healthy controls. The presence of CML, nuclear factor kappa B (NF-kB), the AGE receptor (RAGE), collagen types I, II, VI, and CD68-positive monocytes/macrophages in muscle tissue of 14 patients with FM was investigated.
RESULTS: Patients with FM showed significantly increased serum levels of CML and more CML, activated NF-kB and CD68-positive monocytes/macrophages in the muscle. The collagens and CML were found together, suggesting that the AGE modifications were related to collagen. RAGE was absent in controls but a faint and patchy staining was seen in FM.
CONCLUSIONS: In the connective tissue of fibromyalgic muscles there was more activated NF-kB and more of the CML AGE. Higher CML levels were found in fibromyalgia patients. RAGE was only found in the muscle of fibromyalgia patients – it was not found in those who did not have fibromyalgia.
AGE modification of proteins causes reduced solubility and high resistance to proteolytic digestion of the altered proteins (e.g. AGE-modified collagens).
AGEs can stimulate different types of cells by activation of the transcription factor NF-kB, mediated by specific receptors of AGEs (e.g. RAGE) on the cell surface.
Both mechanisms may contribute to the development, perpetuation, and spreading of pain characteristic in FM patients.
Further discussion and conclusions
One of the challenges in trying to sort out what is going on inside the body is that everything is pretty much related to everything else. NF-kB activation is triggered by RAGE, and then produces more RAGE. There are numerous positive (reinforcing) and negative (dampening) feedback loops.
One question that seems important, but that we can’t begin to answer based on this research, is: why do those with fibromyalgia have higher blood (and tissue) levels of AGE? Genetics? Diet? Environment? We don’t know. Are these AGEs in the blood the cause of higher tissue concentrations, or the result of higher tissue concentrations. We don’t know.
Significance of NF-kappaB and inflammation
But we do know, or at least this research suggests, that whatever the source of higher AGE concentrations in those with fibromyalgia, the reason they become a problem is because they lead to localized ‘hot spots’ of NF-kB over-activation, with resulting inflammation and pain – and that these ‘hot spots’ might reasonably be expected to spread or multiply over time.
NF-kB is the inflammation ‘master switch’ – and it might be that in fibromyalgia the best way to prevent or limit the development of these ‘hot spots’ is via inhibition of NF-kB.
What might inhibition of NF-kB accomplish?
First, inhibition of NF-kB might directly reduce the inflammation (and pain.)
Also, since NF-kB activation is what leads to the production of more RAGE – and the ‘vicious cycle that ensues – inhibiting NF-kB (preventing the formation of yet more RAGE) could put an end to the upward spiral of pain and inflammation.
Therefore it seems reasonable to conclude that inhibition of NF-kB might, by several mechanisms, be of substantial benefit in relieving the chronic pain of fibromyalgia.