The mitochondria have been featured more in and more post-infectious disease research. Health Rising’s first two overviews of recent mitochondrial findings featured long COVID and chronic fatigue syndrome (ME/CFS). Now we turn to fibromyalgia.
Dysfunctional mitochondria can cause pain as well.
The GIST
- Health Rising’s first two overviews of recent mitochondrial findings featured long COVID and chronic fatigue syndrome (ME/CFS). Now we turn to fibromyalgia.
- We usually associate the mitochondria with extreme fatigue, exercise intolerance, and post-exertional malaise, but damaged mitochondria can also produce pain.
- With four studies published in the last year, the mitochondrial field in FM is going through a little boomlet.
- The first study – out of Italy – used the Seahorse XF Cell Mito Stress Test to find the cells of people with FM had a difficult time responding to mitochondrial stress, and put out 20% less energy than the healthy control. People with more severe FM, though, had it much worse. An energy index found they were about 40% in the red compared to healthy controls.
- Next, a Turkish study examining microRNA that negatively impact the mitochondria hit paydirt when it found a microRNA associated with oxidative stress far more commonly found (p<.0010) in the FM patients. That finding suggested oxidative stress – a common mitochondrial inhibitor – was greatly increased.
- The next study provided a potential answer to that issue. An Italian study provided a potential therapy for the high oxidative stress (see Treatment Takeaways below) The researchers induced a fibromyalgia-like state by giving rats a drug called reserpine, which, among other things, increases oxidative stress and knocks out the mitochondria.
- The rats had trouble moving, demonstrated muscle atrophy, reduced mitochondrial enzyme activity, showed decreased activity of most of the complexes in the electron transport chain (complex I, complex III, complex IV), and increased oxidative stress and mitochondrial DNA fragmentation, etc.
- The last study used an electron microscope to find reduced levels of the “cristae” or folds in FM patient’s mitochondria – where ATP production takes place. The authors proposed that the highly reduced ;levels of cristae found resulted from the mitochondria essentially turning itself off and putting the cells in a state of hibernation – much like Naviaux has proposed with ME/CFS.
- They suggested that the mitochondrial dysfunction in FM may impact a broad array of symptoms and tissues including the muscles, nerves, and gut and called the reduction in mitochondrial cristae a “rare and noteworthy’ objective finding.
- Taking the recent ME/CFS, fibromyalgia and long COVID studies together, the last year or so of mitochondrial suggests that a hypometabolic state akin to hibernation exists that may have been triggered a stressor such as an infection which first induced a hypermetabolic state which then essentially burnt out the mitochondria. High levels of oxidative stress are a likely culprit.
- A small but perhaps telling Stanford study found that stimulating the T-cells of ME/CFS patients overloaded their mitochondria, causing increased levels of T-cell death. Indeed energy production has been linked to poor performance of both T and B cells in ME/CFS.
Fibromyalgia, then, brings an interesting twist to the mitochondrial saga in the ME/CFS/FM/long-COVID disease space: mitochondrial problems in FM could be contributing to both exercise and pain and sensory problems.
With four studies published in the last year, the mitochondrial field in FM is going through a little boomlet.
Reduced Energy Production
The latest, “Mitochondrial function in patients affected with fibromyalgia syndrome is impaired and correlates with disease severity“, came out of Italy.
The Italians used the Seahorse XF Cell Mito Stress Test which measures the oxygen consumption (i.e. aerobic energy production) of cells at baseline, during stress, and during mitochondrial enhancement. Researchers can determine such things as mitochondrial respiration, reserve capacity, and the proton leak.
The peripheral blood mononuclear cells of fifty people with FM and 20 healthy age and sex-matched controls were assessed.
The study found a 27% reduction in maximal respiration; the ability of the mitochondria to produce maximal amounts of energy. A reduction in spare respiratory capacity indicated that the FM patients’ mitochondria lacked the reserves to respond to stress that the healthy controls had. An overall assessment of mitochondrial functioning called the bioenergetic health index (BHI) found that the FM patients were about 20% in the red compared to the healthy controls.
Things only got worse with the more severe FM patients. With BHI and spare reserve capacity reduced by another 20%, the more severe patients were looking at a 40-50% functional hit to their mitochondria.
Correlating symptoms (Fibromyalgia Severity Score (FSS)) with the mitochondrial findings, however, produced only a low to moderate finding; i.e. the mitochondrial findings didn’t seem to be contributing that much to fibromyalgia symptoms measured by that test.
Mitochondria on Fire?
One miRNA was greatly increased in the FM patients.
Next, a Turkish study, “Mitochondria miRNAs and Fibromyalgia: New Biomarker Candidates“, isolated and then assessed the gene expression of the mitochondria via microRNAs (miRNAs) in 35 FM patients and healthy controls.
Gene expression studies assess the “state” of the cell, tissue, or in this case, organelle. They tell us what genes are turned on or off, the health of the cell, if it is stressed, and what it’s responding to, etc.
Genes express themselves through the strands of RNA that cells produce. By determining which RNAs get expressed, miRNAs regulate the gene expression of cells.
This Turkish team must have been pretty confident in their idea that the mitochondria are having problems in FM because they honed in on just three mitochondrial miRNAs (mitomiRs): mitomiR-145-5p, mitomiR-223-3p, and mitomiR-23a-3p.
They hit paydirt: the mitomiR-145-5p miRNA stuck out like a sore thumb and was vastly more commonly found (p<.0010) in the FM patients. The miRNA finding suggested a common theme was present – oxidative stress was out of control.
That fits with several recent findings suggesting that damaged mitochondria produce high levels of oxidative stress, which, in turn, damages the mitochondria further, and leads to immune cell exhaustion in ME/CFS.
Boswellia to the Rescue?
The next study provided a potential answer to that issue. Another Italian study, “Impaired mitochondrial quality control in fibromyalgia: Mechanisms involved in skeletal muscle alteration“, induced a fibromyalgia-like state by giving rats reserpine. Reserpine is a nasty chemical that does things like reduce serotonin, norepinephrine, and dopamine levels, increase oxidative stress, hammer mitochondrial production, and enhance inflammation… In other words, it’s perfect!
The authors were primarily interested in the rats’ muscles and central nervous system. FM muscle studies found evidence of muscle damage including ragged red fibers, irregularities in mitochondrial structure, mitochondrial myopathies, and deficiencies in the last complex of the electron transport chain.
Reserpine hit the muscles and the mitochondria hard. The rats had trouble moving, demonstrated muscle atrophy, reduced mitochondrial enzyme activity, showed decreased activity of most of the complexes in the electron transport chain (complex I, complex III, complex IV), and demonstrated increased oxidative stress and mitochondrial DNA fragmentation, etc.
An accompanying spinal and brain study found the reserpines’ activation of glial cells in two key pain regions (dorsal horn of the spinal cord / prefrontal cortex) probably caused central sensitization; the amplification of the pain-producing pathways in the brain.
The FM rats soon had a reprieve, though. Treating them orally with Boswellia gum extract reduced their oxidative stress, decreased their mitochondrial problems, restored mitochondrial enzyme production, increased mitochondrial production, and restored the functioning of one of the complexes.
Increased myogenin production suggested the rats were also now adapting to exercise well. Increased levels of PGC-1α and other factors relating to the production of mitochondria suggested that “mitochondrial biogenesis” – the production of more and more mitochondria, a key part of muscle development – was proceeding smoothly.
Boswellia extract proved to have high mitochondria rejuvenating powers. (The Boswellia tree).
Boswellia extract
Treatment Takeaways
- Boswellia extract reduced the FM rats oxidative stress, decreased their mitochondrial problems, restored mitochondrial enzyme production, increased mitochondrial production, and restored the functioning of one of the complexes.
- Boswellia has been used to treat inflammatory conditions like rheumatoid arthritis, asthma and inflammatory bowel disease. Instead of directly enhancing mitochondrial functioning, Boswellia protects the mitochondrial enzymes and the electron transport chain from the ravages of oxidative stress.
- Interestingly, when asked about Boswellia and the mitochondria, AI ChatGPT stated that Boswellia’s ability to enhance ATP production is “especially relevant in diseases associated with mitochondrial dysfunction, such as chronic fatigue syndrome and fibromyalgia, where fcellular energy demand often exceeds supply.” (!)
Boswellia has been used to treat inflammatory conditions like rheumatoid arthritis, asthma and inflammatory bowel disease. Instead of directly enhancing mitochondrial functioning, Boswellia protects the mitochondrial enzymes and the electron transport chain from the ravages of oxidative stress.
Given the evidence suggesting that oxidative stress is indeed damaging the mitochondria in ME/CFS, Boswellia might come in handy. Lord knows we need better antioxidants.
Interestingly, when asked about Boswellia and the mitochondria, AI ChatGPT stated that Boswellia’s ability to enhance ATP production is “especially relevant in diseases associated with mitochondrial dysfunction, such as chronic fatigue syndrome and fibromyalgia, where cellular energy demand often exceeds supply.” (!) ChatGPT concluded, “These effects make it a potential therapeutic tool for managing conditions characterized by mitochondrial dysfunction, such as fibromyalgia, neurodegeneration, and chronic inflammation.”
The authors concluded that antioxidants like Boswellia extract that can protect the mitochondria should get more study in FM.
Hibernating Cells in Fibromyalgia as Well?
The reduced numbers of cristae (folds) suggested to the Israeli researchers that the mitochondria in FM patients’ cells were in hibernation.
This small (n=14) Israeli study, “Mitochondrial structural alterations in fibromyalgia: a pilot electron microscopy study“, didn’t assess mitochondrial functioning; instead it used transmission electron microscopy (TEM) to peer deeply into the structure of the mitochondria in FM. It suspected that high levels of oxidative stress were directly damaging the mitochondria.
The reduced levels of mitochondria found suggested that mitochondrial turnover, or biogenesis, was impaired. Reduced levels of the inner mitochondrial folds, or cristae, where the electron transport chain is found and where ATP production takes place suggested energy production was down. Indeed, the authors reported that “partial or full loss of cristae integrity” was seen in many FM patients’ cells. The authors proposed that the damage could result in increased oxidative stress.
Despite the small sample size, the authors were surprised the low cristae levels correlated with pain intensity; i.e. the more reduced the cristae were, the more widespread pain the FM patients reported.
Citing not Naviaux but other authors, including Brian Walitt (!), they proposed that the cristae abnormalities reflected a “hibernation-like state” the mitochondria had developed to survive “stressful events”. (It was astonishing to learn that mitochondrial hibernation had been proposed in FM in 2018).
They proposed that mitochondrial dysfunction, plus decreased ATP production, compelled cells to enter into a state of hypometabolism or “metabolic dormancy”. They suggested that the mitochondrial dysfunction in FM may impact a broad array of symptoms and tissues including the muscles, nerves, and gut.
Calling the reduction in mitochondrial cristae a “rare and noteworthy’ finding of objective pathology, they called for larger studies.
Conclusion
The FM studies were all small, all came from Europe and all made sense given what we’ve learned recently from the overview of recent ME/CFS and long-COVID studies.
https://www.healthrising.org/blog/2024/10/24/mitochondria-long-covid-core-problems/
Mitochondrial energy production appears to be down significantly – particularly in more severe FM patients – and high levels of oxidative stress could help explain why. It turns out that the hibernating mitochondria/hypometabolic hypothesis – something we’ve long associated with ME/CFS – popped up in fibromyalgia six years ago.
But do the recent fibromyalgia mitochondrial findings fit with recent ME/CFS and long-COVID findings? They do.
These studies not only found a hypometabolic state was present but suggested that a hypermetabolic state associated with increased oxidative stress preceded it. One case study proposed that the increased oxidative stress caused by a herpesvirus infection caused a heritable mitochondrial mutation to be unearthed – resulting in a severe case of ME/CFS. A small but perhaps telling Stanford study found that stimulating the T-cells of ME/CFS patients overloaded their mitochondria, causing increased levels of T-cell death.
Once again, we were back to a similar scenario: damaged or dysfunctional mitochondria which can’t “take the heat” when stressed produce large amounts of oxidative stress. The successful FM animal study employing Boswellia extract suggested that oxidative stress was indeed a big deal. Finally one of the FM studies took the process a step further by proposing cells are shutting down (reducing the number of mitochondrial cristae) and hibernating to reduce the stress they’re experiencing.
On the downside, these studies tend to be small. On the upside, they appear to be pointing in similar directions.
BIG (little) Donation Drive Update
Why do we cover all these diseases? Because we believe the clues to all of them are found in each of them.
Thanks to the over 180 people who have contributed to Health Rising’s End of the Year donation drive.
This blog – the last of three to look at the mitochondria in ME/CFS, long COVID and FM – illustrates a core feature of Health Rising – an attempt to look across all these diseases for commonalities. The commonalities found thus far suggest that if you can solve one disease you can probably solve them all – and that’s why we take the time and trouble to do this. If that’s what you want to see please support us!
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Def using naltrexone every hour stops all fibro,,I have zero pain. 4.2mls every hour. It’s a Wonder drug, I’m hoping now that by resting whist using might be able to reverse the hibernation, freeze response, I read that about rats years ago, the freeze response.
I just googled Naltrexone. It says it is used for alcohol addiction. If it works for fibromyalgia, I would love to try it. I’ve been struggling with it for 28 years. Since I was 11. Nothing relieves it to hear someone say something works on fibro pain is amazing!
Is that LDN? Can I ask where you got it from please? thanks
You need a script from yr doctor, for large amounts which is what’s usually needed, it’s best to pose as a alcoholic, unless you have a open minded doctor, it Def dosent work once a day for me anyways and my followers.
Hello Vanessa, how many mg Naltrexone do you take in 24 hours?
I tried it a while but maybe not the right dosis.
Frank
Hey Frank, I’m using about 4.2 mls every hour that the same as mgs, so 4 to 5mgs, i just have to stretch out my available naltrexone over 24 hrs.
It’s better if you can add some caffiene, small amounts. Be aware not to overdo things in the endorphin stage. It’s the blockade stage at first that’s the better time to get moving done.
Today I’m starting twice a day LDN for FM and POTS. My physician told me to “play around with it “ to find my sweet spot and dosing schedule. I was using it nightly but it was a wearing off too soon. Switched to evening with same results. Then I did noon. The pain relief seemed longer. I’m only taking 0.5mg. I haven’t been able to dose up from it because it caused me worsening TMJ and headaches. I’m splitting my 0.5mg (0.25mg) to morning and afternoon To feel what that does. It seems to help with pain and fatigue.
Frank, Tell me a little bit about how you were using it?
Hi ,yr body is used to .5 so best to take that at all doses ,but up to you, it only last for a short time then leaves the body hence I use it hourly ,I’ve been experimenting for 3 years now, if you want my original abstract protocol, email me vgray1221@gmail.com
All the best .
Hi Cort, does the study mention any specific amount of boswellia?
I had an unbelievable visit to my ENT this week. I have been wearing hearing aids for 3 years, but my hearing had deteriorated quite a lot after I had Covid twice in the same year.
A young doctor of audiology fitted me with some stronger hearing aids that seem great so far.
She actually knew about ME/CFS and how it can affect hearing. Now it seems that Covid can be even worse.
“Sensorineural hearing loss associated with Covid”.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10072149/#:~:text=COVID%2D19%20can%20damage%20the,symptom%20of%20long%20COVID%2D19.
Hearing loss can be the only symptom after even a mild case of Covid so visit your ENT if you have any doubts.
One interesting thing she said was that with ME/CFS, you may be hearing what is said but have trouble processing it.
Since the doctor is a new graduate from the University of Florida, my hope is that medical schools are starting to take ME/CFS seriously.
I had an unbelievable visit to my ENT this week. I have been wearing hearing aids for 3 years, but my hearing had deteriorated quite a lot after I had Covid twice in the same year.
A young doctor of audiology fitted me with some stronger hearing aids that seem great so far.
She actually knew about ME/CFS and how it can affect hearing. Now it seems that Covid can be even worse.
“Sensorineural hearing loss associated with Covid”.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10072149/#:~:text=COVID%2D19%20can%20damage%20the,symptom%20of%20long%20COVID%2D19.
Hearing loss can be the only symptom after even a mild case of Covid so visit your ENT if you have any doubts.
One interesting thing she said was that with ME/CFS, you may be hearing what is said but have trouble processing it.
Since the doctor is a new graduate from the University of Florida, my hope is that medical schools are starting to take ME/CFS seriously.
I lost my hearing after an RSV infection 2 years ago. It has mostly returned but not completely. The ENT said to wait until it stabilized before getting hearing aids. It’s on the list. Sigh…. I also have long covid and recently diagnosed with fibromyalgia
I’m sorry you’re experiencing hearing loss. I’m amazed your ENT medic is making a causal link when research is so minimal.
Just to give some perspective, the ear mechanism wears out as we age, just like every single body mechanism.
So by age 50, 40% of people will have a degree of sensori-neural hearing loss. And by 70, 70%. A few more people will have profound loss but this is more rare.
Sensori-neural is the brain side of the mechanism…. cochlear, auditory nerve etc. so nothing to do with wax/ eustachian tube/ middle ear congestion.
A huge number of elderly people won’t make friends with their hearing aid and since there is no cure for sensori-motor loss, the individual will choose to see an audiologist or not.
Everyone with hearing loss…conductive or sensori-neural…hears a certain amount but struggles to process information. This is because loss is not uniform across all frequencies. Low frequencies remain pretty much intact, and loss is in the frequencies where human speech lies… known as the speech banana on the audiogram.
Jane, This published paper is not based on “minimal research”. This is not the only study to associated hearing loss with Covid.
“Many authors have shown that COVID-19 can lead to ENT disorders. ENT symptoms are known in COVID-19, but little information is available about damage to the hearing organ. Osman Kilic et al12 indicated in their publication the relationship between hearing loss and COVID-19. SSNHL after COVID-19 is mainly reported in the form of case reports. Fance et al13 confirmed hearing loss in 40.5% of patients after COVID-19, diagnosing one-sided or bilateral sensorineural hearing loss. In the discussed publication, sensorineural hearing loss was confirmed in 65.5%, also confirming unilateral or bilateral hearing loss. However, one-sided changes were more frequent, as in other publications.12,14–16 Bilateral hearing loss may be caused by the harmful effects of COVID-19 on the outer hair cells of the cochlea.17 On the other hand, in another study evaluating hearing in long COVID-19 patients, air conduction thresholds showed a typical threshold for the average age of the subjects.18 This study shows that tinnitus and vertigo are significantly more common than hearing loss in long COVID-19.18”
My comments about my own hearing loss were that I had a rapid decline after Covid. Of course, many factors may cause hearing loss: congenital defects; untreated bacterial infections; viruses; injury; persistent loud noise and the ageing process. But, the mean age in this study was 48 and the hearing loss was not detected until after Covid.
A few random observations:
1. My Google search revealed that Boswelia is frankincense, which, along with gold and myrrh, was a git from the Magi in the historical/biblical account of Jesus’ birth. It seems serendipitous coming across this info so close to Christmas and hopeful so close to the New Year.
2. For the first time ever in doing a Google search I used the term “ME/CFS” instead of “chronic fatigue syndrome.” To me, my own behavior suggests that the prevalent terminology is changing and that the illness is being accepted as “real” and “significant” and “scientific.”
3. What’s up with the Donation Drive thermometer? It doesn’t seem like it has moved in more than a week.
I have never heard of Boswellia & will look it up.
I am very worried to to references from ChatGPT. This is a known unreliable resource and I genuinely don’t think we should be quoting from it or any AI, when people’s health is at stake.
I would also like to know if any amount of Boswellia was mentioned. I’ve been using LDN for several years and after a bout with covid last year, it seemed to stop working. However, I found a LDN FB group that suggested skipping one day a week might help and since trying that it seems to be helping again. Fibro fog gone, but still dealing with some pain. If Boswellia can help me more, I’d like to know how much to take and whether I need to start with a small amount and build up. Thanks for all you do, Cort! I’ve mailed you a check-I’m old school!
I am very much liking this research. I have had CFS and Fibro since 1986. Over a 30 year period I studied medical papers and considered/investigated every possibility that I could find in search of explanations and treatment. Treatment trials included hormone therapies, diets to heal a damaged gut lining, diets and supplements to enhance my immune response, and others to dampen it. I tried everything suggested by any source that was reasonably reputable, as long as it was reasonably safe and affordable. None of these treatment trials helped (except a temporary resolution of all symptoms in response to a multi-drug 3 week regimen for H.Pylori – even though I had tested negative for it. I am still not sure why this resolved all symptoms, until I stopped abx meds). The main lesson that all of the other many treatment trial failures taught me – is that my symptoms are caused by something more basal or core to my metabolism.
While I had/have (unexplained) abnormalities in my neuro, gastro, endocrine, immune and vascular functions – addressing any ONE of these system abnormalities always failed. I came to realize that human biochemistry is so complex and interactive that if any one of these systems is significantly deregulated, it will deregulate common biochemistry that WILL deregulate all of the other systems (or keep them deregulated). Thus, addressing any ONE of these (significantly deregulated) systems is not apt to recover our health.
This led me to the confounding question of; “What problem could be deeper – more basal and core – such that it could affect all of these systems (and probably more)?”
Slow and deficient energy production in many, most or all cells – could explain why CFS and Fibro (and perhaps Long Covid) could undermine the proper function of any (and perhaps every) system in our bodies (to explain our multi-system symptoms and abnormalities). It could also explain our major subjective symptom of low energy stamina and PEM. That is why I think that this avenue of research could possibly uncover the core of all of our symptoms (rather than just another secondary imbalance – that is largely unresponsive to treatment). It is especially refreshing to be informed of a tested (safe and inexpensive) supplement to trial for ourselves (Boswellia). I hope that any who try it might please report their experience (success, failure or intolerance) to the rest of us.
To further support the potential of this research (for me personally), approx 25 years ago I had quite extensive testing done by Genova Diagnostics Labs. One of the reports stated that I had unusually high oxidant levels (and a genetic predisposition to a lower than normal production of our main anti-oxidant – glutathione). The report suggested that this weakness or deficiency might (at least partially) be offset by extra anti-oxidants in the diet. This seems to support the potential benefits of Boswellia that one of the researchers reported.
Thank-you again Cort – for your excellent synopsis. My energy is now too limited to monitor all possible sources to keep up on research, so I am so thankful for your endless work on our behalf.
It would be a great help if people posting could state where they are from.
It often feels as if the US has zero awareness of the rest of the world and there are big differences.
Thank you.
I’m UK.
took Boswellia about 5 years ago to get my bowels under control again. I didn’t tolerate it well and can’t report any success. It didn’t even have any real effect on my intestinal complaints. I have had much greater success with a ketogenic diet.
There are also supposed to be differences in Boswellia, depending on which country it comes from.
Unfortunately, I have not had any success with it, although I have tried it several times. Different brands, in different dosages and with and without other supplements.
Translated with DeepL.com (free version)
There has been a recent webinar on
MCAS Mast Cell Activation Syndrome
which has just been posted on Youtube. One of Dr. Bob Naviaux’s former team members, Dr. Eric Gordon hosted this webinar by an expert in MCAS.
https://m.youtube.com/watch?v=lTp-1RuE6_4
I dont mean to make a comment irrelevant to this blog, but it is the only effective way to make you immediately aware of this resource.
Interesting. One reason that Pregabilin is helpful for Fm patients is that our GABA is naturally low, and GABA is critical for good sleep.
This article suggests a connection between mitochondria and GABA:
https://pubmed.ncbi.nlm.nih.gov/32200800/