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The Hibernation Diseases?

Mitochondrial Finding Suggests Fibromyalgia May Be Hibernation Disease as Well
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Reprinted with the kind permission of Cort Johnson and Health Rising

Nothing happens in your body without some of your genes going off like skyrockets.  If your body is responding to something – or acting differently in some way – it should show up in a different pattern of gene expression.

If you get a virus, for instance, the virus will trigger or wake up certain immune genes which will then tell your cells to start producing cytokines or other immune factors. That unusual level of immune gene expression can then be picked up in a study.

Unusual patterns were what these researchers were looking for in this fibromyalgia gene expression study. They certainly found them, and a common theme emerged as well. The results suggest that fibromyalgia with its pain and fatigue, and chronic fatigue syndrome (ME/CFS) with its fatigue and pain, are looking more and more like sister diseases all the time.

The Study

J Pain Res. 2018 Nov 21;11:2981-2990. doi: 10.2147/JPR.S169499. eCollection 2018.  A predictive algorithm to identify genes that discriminate individuals with fibromyalgia diagnosis from healthy controls. Lukkahatai N, Walitt B, Deandrés-Galiana EJ, Fernández-Martínez JL, Saligan LN.

This fibromyalgia study used an algorithm from a previous study by the authors that attempted to identify which cancer patients would develop severe fatigue after radiation treatment. Just as an otherwise ordinary infection can have a debilitating effect on some people with ME/CFS, radiation has a similar, fatiguing effect on some cancer patients. The radiation study was novel in that it assumed that a wide array of synergistically acting genes was responsible for the fatigue, and it used an algorithm which looked for clusters of genes which worked together. Interestingly, it found the fatigued group was characterized by reduced gene expression. Somehow the radiation treatment had turned some of their genes off.

Interestingly, Nancy Klimas found a similar pattern in a network analysis of ME/CFS. In contrast to people with Gulf War Illness, the immune networks of people with ME/CFS lacked connections and were subdued. It was almost as if the immune system had, in some ways, turned itself off.

This study used the new algorithm to reanalyze the results from a prior study of women with FM. The goal was to be able to differentiate FM patients from healthy controls, and it was successful in doing that. First, studies like this typically bring up dozens or hundreds of genes. They do a pathway analysis in an attempt to determine which pathways in the patients’ bodies are most up or down-regulated.

This study found that a group of 57 genes were best at discriminating people with FM from healthy controls. Those genes were associated with a number of different pathways. Two genes from that group were most highly discriminative; i.e. their expression in the fibromyalgia patients was so different from the healthy controls as to make them stand out.

The results are preliminary – the authors warned that much larger studies are needed to validate them – but are fascinating nonetheless. As with fatigued prostate cancer patients, both genes that stood out in the fibromyalgia patients were down-regulated.

The MRPL4 (mitochondrial ribosomal protein L4) gene encodes proteins needed for the mitochondria to work properly. The down-regulation of this gene suggested reduced mitochondrial functioning may be present in FM.

This is not the first time that problems with the mitochondria – the engines of energy production in our cells – have been suspected in FM. Problems with vigorous exercise, fatigue and pain are, in fact, common in mitochondrial disorders.

A small family study suggested that a mutation in a mitochondrial gene – and the resulting increase in oxidative stress – could be playing a large role in some people with FM and suggested that future studies concentrate on people with family histories of the disease on the mother’s side.

An examination of connective tissue cells called fibroblasts found evidence of decreased mitochondrial biogenesis (fewer new mitochondria), reduced oxygen consumption, decreased antioxidant enzyme expression and mitochondrial dysfunction. Several studies of skin cells have found evidence of mitochondrial dysfunction including reduced energy production and increased oxidative stress.  The authors suggested that inflammation, increased oxidative stress and mitochondrial problems were responsible for the allodynia – the hypersensitivity to even light touch – often found in FM.

A 2013 review suggested that high levels of oxidative stress (damage by free radicals) are, by impairing mitochondrial function in the muscle and nervous systems of FM patients, causing widespread pain and central sensitivity. Significantly, lower levels of intramuscular ATP, phosphocreatinine (PCr) and fat content pointed to significant problems with the mitochondria in the muscles of FM patients.

That’s just in the past five years. At least five studies before that suggest mitochondrial problems are present in fibromyalgia.

The other gene that stood out was SLC38A (sodium-coupled neutral amino acid transporter), which couldn’t have been a surprise at all. This gene (like most genes) has several functions, including energy metabolism, detoxification, neurotransmitter cycling and nutrient uptake. It encodes a protein called S38A1 which plays a role in the transportation of glutamine, a precursor of the excitatory neurotransmitter glutamate, which has long been suspected of playing a role in FM and fatigue states. The down-regulation of this gene doesn’t seem to jive with the hypothesis that increased levels of central nervous system glutamate are causing pain in FM.

Glutamate is also used as a fuel in the central nervous system, however, and glutamine plays a major role in energy production. Glutamine is the precursor of α-ketoglutarate, which is oxidized to produce the substrates that ultimately produce glucose.

The under-expression of SLC38A in FM, then, if it’s validated, could have major consequences for several systems in the body.

The Hibernation Diseases?

The general pathways identified provided more evidence for the role impaired energy production may play in fibromyalgia. Genes associated with the Akt pathway, which regulates energy metabolism, were markedly down-regulated. This pathway is activated, interestingly enough, by an enzyme, PDK, which is down-regulated during hibernation in animals. PDK suppression during this time results in markedly reduced mitochondrial functioning.

This suggests that the energy metabolism system in FM may be in a state of hibernation. That, of course, sounds eerily similar to Robert Naviaux’s dauer model, which proposes that people with chronic fatigue syndrome (ME/CFS) exist in a hibernation-like state characterized by low energy metabolism.

The other highlighted pathways were involved in inflammation, which given recent findings of neuro and systemic inflammation, was no surprise.

Conclusion

The authors emphasized that no clinical conclusions could be drawn from this decidedly preliminary result and that larger follow up studies are needed.

How intriguing it is, though, to see the idea of a state of hibernation arrived at from two different starting points: from a gene expression study in fibromyalgia and from metabolomic studies in ME/CFS.

The fact that a similar constellation of factors – oxidative stress, mitochondrial dysfunction and inflammation – are showing up in both fibromyalgia and chronic fatigue syndrome is encouraging as well. Time will tell with both these diseases, but a general theme may be emerging.


About the Author: ProHealth is pleased to share information from Cort Johnson.  Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.

 

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