The muscles, the mitochondria and fibromyalgia – what a potentially potent mix. Over the past six months, at least three fibromyalgia muscle studies have popped up. (Health Rising has reviewed all three). Plus, a study examining energy production problems in fibromyalgia (FM) just appeared.
- Painfully High Muscle Pressures in Fibromyalgia Put Old Paradigm to the Test – Health Rising
- Muscle Study Finds Key Differences in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)
In his 2020 Swedish study, “Evidence of Mitochondrial Dysfunction in Fibromyalgia: Deviating Muscle Energy Metabolism Detected Using Microdialysis and Magnetic Resonance“, Gerdle et al. took the study of the muscles in FM to new heights.
Gerdle had last studied energy metabolism in FM in his 2013 study, “Decreased muscle concentrations of ATP and PCR in the quadriceps muscle of fibromyalgia patients–a 31P-MRS study – PubMed (nih.gov)“. That study found substantially reduced muscle ATP and phosphocreatinine (30%) concentrations in the quadriceps muscle. It concluded that the abnormalities probably resulted from a combination of inactivity and dysfunctional mitochondria.
The authors, though, seemed to be reaching a bit with the inactivity conclusion. The (rather simple) activity assessment they used in the study indicated that the FM patients and the healthy controls had similar activity levels.
They’d also concluded that the FM group has normal aerobic capacity, but the exercise test (1 day submaximal exercise test) they used has produced misleading results in chronic fatigue syndrome (ME/CFS).
Despite the fact that the BMIs (body mass indices) of the two groups were similar, they also suggested that the higher intramuscular fat levels found in the muscle may have the reflected the higher percentage of obese individuals in the FM group.
After suggesting that fat, inactive FM patients may be contributing to their findings, the authors swung, though, to a fascinating possibility – that even though they were less active, FM patients might still be “overusing” their muscles.
They suggested that psychological factors (high persistence behavior (i.e. overly hard-driving FM patients)), plus studies showing that FM patients’ muscles do not relax in between muscle contractions, plus another study showing an apparently abnormal “activation pattern(s)” (unexplained) suggested that FM patients might be overusing their muscles even as their activity levels suggested they were underusing them.
The authors, it should be noted, also suggested that mitochondrial problems could be causing the reduced muscle ATP and PCR concentrations, and the increased concentrations of lactate and pyruvate that some studies have found.
To be fair, the authors simply seemed to be covering all the bases. More than anything, with these researchers swinging from one hypothesis to the other, this 2013 study simply seemed to show how in flux the muscle field of FM was.
What was causing the strange muscle findings in FM? Was it inactivity, abnormal muscle activation patterns, mitochondrial issues or all of the above? Nobody knew.
Findings Coalesce – the 2020 Study
Seven years later, the group published a study designed to make up for shortcomings in FM muscle studies. It was larger (n=64) (but not all that large), assessed metabolic status in two places (trapezius, erector spinae muscles), assessed blood flows, and used more comprehensive statistics.
Sometimes it’s hard to tell if a field is making progress. Eight years later, it’s clear that step by step, study by study, this aspect of fibromyalgia research has made real progress.
The time, the authors lead off the discussion with the rather definitive statement:
The more sophisticated analyses the researchers used found that it was biology (lower ATP/PCr, PCr/Ptot, Pi/PCr), rather than something like obesity, which differentiated the FM patients from the healthy controls. Plus, this time, abnormalities found were clearly associated with increased pain.
“FM was clearly associated with higher levels of pyruvate and lower levels of ATP and PCr, a finding that suggests muscle mitochondrial dysfunctions in FM.”
Noting that this was the fourth study to find so, the authors reported that FM “seems” to be associated with increases in pyruvate and lactate – two products of glycolysis.
That’s a very interesting finding given the similar findings that have shown up in chronic fatigue syndrome (ME/CFS). Pyruvate is the end product of the first half of the energy production program (glycolysis/anaerobic energy production). It is converted into acetyl-CoA, which is transported into the mitochondria where it’s used, in a series of five complex steps, to produce massive amounts of ATP (aerobic energy production).
The higher levels of pyruvate and lactate (a breakdown product of pyruvate) found in the FM patients’ muscles suggest that pyruvate is not getting properly metabolized, thus depriving the mitochondria of the fuel they need.
The lower levels of ATP and phosphocreatine (PCr) found in the FM patients validated that idea. (PCr is important for the muscles as it “shuttles” a phosphate from ATP to the them).
- Numerous studies have found muscle abnormalities in fibromyalgia dating back for decades
- This Swedish group’s 2013 study found signs of mitochondrial dysfunction (low ATP, PCr) in the muscles of FM patients. The authors pointed to a variety of different factors that might have come into play (mitochondrial problems, muscle overuse, inactivity, obesity).
- Seven years later the authors returned with a bigger, more effective study – and a stronger conclusion. They again found evidence of reduced ATP and PCr as well as increased pyruvate. Similar findings have shown up in chronic fatigue syndrome (ME/CFS)
- With proteomic, metabolomic and other studies coming to similar conclusion the authors concluded that mitochondrial problems are present in FM.
- They also proposed that mitochondrial problems are playing a role in chronic pain in general and noted that pain is common in people with primary mitochondrial disorders.
- The authors also reported that reduced ATP levels have been found in a wide variety of tissues including the muscles, skin, plasma, platelets, nerve and immune cells.
- While obesity was increased in FM the analyses suggested it had no impact on the muscle issues found.
- An altered phosphorous/PCr imbalance and increased pyruvate levels seemed to particularly impact pain levels.
- The authors suggested that a variety of factors may be in play including oxidative stress and mitochondrial induced inflammation.
The authors proposed that mitochondrial problems were likely the problem – not just for FM patients – but for others who experience chronic pain. (They also noted that chronic pain is common in people with mitochondrial diseases). They aren’t the first to propose that and, in fact, proposed that possibility in the 2013 paper, but now have much stronger legs to stand on. At least six studies from the past couple of years have come to the same conclusion. That those studies are coming to similar conclusions from different directions (proteomic, metabolomic, urine metabolite studies) – suggest that the finding is a robust one.
When it came to explaining the findings, the authors were, again, at something at a loss. They noted that aging and obesity – neither of which could explain FM (plenty of young people have FM, and plenty of obese people do not) are associated with mitochondrial problems.
While higher rates of obesity were found in the FM patients (FM – 27.3% overweight, 42.4% obese/severe obese; controls – 22.6% overweight, 6.5% obese/severe obese; p < 0.001) but the multivariate statistics suggested it played no role in the FM patients. (Increased BMI in both groups, though, was associated with reduced PCr ATP and pyruvate levels.) In this larger study, the submaximal exercise test also suggested that aerobic capacity was lower in the FM patients.
Given the possible connection between altered circadian rhythms and mitochondrial activity, they suggested that poor sleep in FM might play a factor. They also brought up the possibility of overactive muscles.
The authors also noted that the low PCr levels were throwing the PCr/phosphorous balance off – affecting blood flows and pain levels. Regression analyses indicated that fifty percent of the pain intensity could be explained by problems with blood flows and the metabolic abnormalities. The phosphorous/PCr imbalance and the increased pyruvate levels were particularly important factors.
They noted that another study found that proteins associated with mitochondrial production were strongly implicated in the production of pain. (Interestingly, a large cytokine study found that cytokines were not.)
In the end, the authors painted a complex picture in which increased oxidative stress, mitochondrial-induced inflammation, a mitochondrial-produced “damage-associated molecular pattern” which triggers inflammation, NLRP3 inflammasomes that tweak sensory neurons, and others could be involved.
In their conclusion, the authors noted that they’d found significant metabolic and blood flow alterations in the muscles of FM, which may result from dysfunctional mitochondria in the muscles. After the pages of dense biological discussion, it was strange to see the authors revert to their tropes from eight years ago.
“Although it is unclear why muscle mitochondrial dysfunctions are found in FM, inactivity, obesity, aging, and pain per se may be involved.”
Perhaps the editors of the journal demanded it.
All of this brings up an intriguing question: With all the evidence of ATP and muscle problems that have been found in FM, why does exercise seem to work – and how well does it work?