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Muscles chronic fatigue syndrome

It would seem remarkable if the muscles were not affected in ME/CFS – and indeed French and Italian researchers have been focusing on them.

The muscles. Is there any tissue more likely to be affected in such an exertionally challenged disease?

We just saw NIH researchers undercover a possible mitochondrial abnormality in the muscles of people with chronic fatigue syndrome (ME/CFS). With rather impeccable timing, Yves Jammes – one of the few ME/CFS muscle researchers – is back!  A professor of physiology at Aix-Marseille in France, Jammes has managed to publish 8 studies mostly on the muscles in chronic fatigue syndrome (ME/CFS) since 2005.

Over in Italy, Stephania Fulle has been exploring muscle issues in ME/CFS for over 20 years. In the very small muscle studies section of ME/CFS research, they’ve been a ray of light in the darkness.

WASF3 – NIH Researchers Find New Mitochondrial Abnormality in ME/CFS

It’s time to do a little catch-up.

Two Different Types of Fatigue

Two different types of fatigue – central and peripheral fatigue – have been illuminated. It might not be surprising to anyone with ME/CFS that both have been found in this disease.

Central fatigue is produced by the brain and refers to the inability of the brain to get signals to the muscles to work. At least four studies have found evidence that central fatigue is present in ME/CFS. Both kinds of muscle failure – peripheral and central fatigue – have been found in ME/CFS.

“Peripheral muscle failure” is produced in the body. It can result if the muscles aren’t getting enough oxygen, if the muscles aren’t responding to nervous system signals, and/or if a damaged muscle membrane is present. Peripheral muscle fatigue is often closely linked to high levels of free radicals or reactive oxidative species. At least 4 studies have found evidence that peripheral fatigue is present in ME/CFS.

This blog is focused on peripherally produced fatigue.

Damaged Muscle Cell Membranes 

Evidence of muscle membrane damage has been accumulating in ME/CFS for decades.

Evidence of muscle membrane damage has been accumulating in ME/CFS for decades.

Fulle and Jammes have been focusing on potential problems in muscle cell membranes in ME/CFS for almost 20 years. They’ve often analyzed the M-waves produced by the muscles as they contract and return to form during exercise.

The M-wave analyses Fulle and Jammes typically use assess how well the muscles are being activated during a fatiguing exercise. Reduced M-wave activity is typically associated with problems with damage to the sarcoplasmic reticulum – the membranes that store the calcium ions that enable the muscles to contract.

Stephanie Fulle got the muscle issue in ME/CFS off to a good start in 2000 when she found evidence of oxidative stress- (free radical) induced damage to the DNA and lipids (read muscle cell membranes) in the muscles of people with ME/CFS. That made sense as studies have shown that exercise creates much more oxidative stress in people with ME/CFS. Plus, numerous studies have found increased oxidative stress levels at rest in ME/CFS as well. Whatever else ME/CFS is, it is a disease of increased oxidative stress.

In 2003, Fulle found evidence that the membranes of the sarcoplasmic reticulum – which store the calcium muscles need to react – had been damaged. When calcium levels in the muscle cells rise, they contract. When they move back into the sarcoplasmic reticulum, the muscle cells relax. It’s this contraction-relaxation process that produces muscle activity and force.

She also found problems with both the (Na(+)/K(+) ionic pump involved in muscle cell excitation and muscle cell contraction as well as the Ca(2+)-pump involve in muscle cell contraction in ME/CFS. At a quite fundamental level then, the muscle cells in ME/CFS were not looking good.

Jammes’s small 2005 study started off his long interest in oxidative stress, muscle membrane excitability (m-wave amplitude), and exercise in ME/CFS. His finding – that high rates of oxidative stress were associated with reductions in muscle membrane excitability (the ability of the muscles cells to respond) in ME/CFS led him to conclude these two “objective signs of muscle dysfunction are sufficient to explain muscle pain and post-exertional malaise reported” in ME/CFS.

In 2008, Fulle proposed that “specific critical points in the muscle” were being affected by free radicals (reactive oxygen species) in ME/CFS. Her 2009 study also found that a switch to “fatigue-prone, energetically expensive” muscle fibers had occurred in ME/CFS. (A similar switch has been found in fibromyalgia.)

The first gene expression (or transcriptome) analysis of muscle tissues done in ME/CFS in 2009 suggested that the muscle cell studies were on the right track. Altered genes involved mitochondrial and oxidative stress, energy production, muscle structure, and muscle fiber type.

oxidative stress

High levels of oxidative stress damaging muscle membranes have been a theme from the beginning.

THE GIST

  • The muscles showed up in a big way in the last blog on a potential muscle mitochondrial connection in ME/CFS.
  • While one would think that muscles might have been a big deal in such an exertionally challenged disease, they’ve never been front and center.
  • Yves Jammes and Sofia Fulle – a French and an Italian researcher – have been studying the muscles in ME/CFS for over 20 years though. With Jammes publishing a recent paper, and with interest in the muscles heating up, it’s time to see what they’ve found.
  • They’ve both been focusing on potential problems with the muscle cell membranes. It turns out that the muscle membranes – particularly the sarcoplasmic reticulum – which hold the calcium that the muscles need to contract – are highly susceptible to oxidative stress.
  • Studies of electrical fields called M-waves are used in many studies to assess how well the muscles are responding to fatigue, and studies show reduced M-wave activity in ME/CFS. Studies suggest that the more reduced the M-waves are, the more post-exertional malaise and symptoms ME/CFS patients exhibit, and the less able they are to provide muscle strength. (Note, though that not everyone with ME/CFS has reduced M-waves, but the people who are are sicker).
  • Since healthy muscle membranes are essential for proper M-wave activity, the reduced M-wave activity found – even at rest in ME/CFS – has pointed a finger at the muscle membranes.
  • Indeed, damaged muscle membranes have been found. High levels of “oxidative stress” (free radicals) are most likely the cause of the membrane damage in ME/CFS and Jammes has found a possible reason why – low levels of the protective heat shock proteins that should be protecting the membranes.
  • In fact, high levels of free radicals (or reactive oxygen species) could be producing much in ME/CFS. Paul and Lemle propose that an infection-triggered mitochondrial breakdown in long COVID and ME/CFS disrupts the redox (oxidative stress) balance, and produces massive levels of free radicals, which then feed an inflammatory process that impacts the blood vessels, the brain, the muscles, etc.
  • Indeed, while Jammes and Fulle have been pointing a finger at the muscle membranes for two decades now, recent research has been focusing more and more on damage to the membranes that surround our cells.
  • With 2 major Open Medicine Foundation-funded muscle studies, as well as further NIH muscle work, and a Solve M.E. Ramsay muscle study underway, the muscles are finally becoming something of a hot topic in ME/CFS research. We will hopefully learn much more about them in the near future.

 

 

By 2009, Jammes was asking himself why oxidative stress was having such an effect on the muscle membranes in ME/CFS. His very small 2009 study suggested that low levels of the heat shock proteins that protect the membranes were present. Plus, he provided more evidence that damaged muscle cell membranes were present in ME/CFS as well. His much larger 2012 study (73 patients) validated his 2009 results.

In 2020, Jammes proposed something radical. While exercise – which produces lots of oxidative stress – might be expected to damage the cellular membranes in ME/CFS – being in a restful state certainly shouldn’t. Jammes found, though, altered M-wave activity not just in exercising muscle in ME/CFS but in resting muscle as well.

Plus, his study provided evidence that oxidative stress levels were indeed associated with the ability of the ME/CFS patients’ muscles to respond to exercise. Both before and after exercise the muscles of ME/CFS patients with higher oxidative stress levels responded more poorly.

It was not surprising then, to see Jammes propose that high oxidative stress levels were causing a “systemic disorder of muscle membrane excitability” in ME/CFS. As Fulle had earlier, he proposed that the crucial Na+–K+ pump that regulates the muscle contraction process was failing. (These pumps are found in cells across the body and are susceptible to oxidative stress. Jammes asserted that this “strongly suggests that sarcolemma fatigue (read muscle membrane problems) is responsible for the post-exercise muscle force failure” in ME/CFS.

Jammes’s 2023 paper, “Consequences of sarcolemma fatigue on maximal muscle strength production in patients with myalgic encephalomyelitis/chronic fatigue syndrome“, asked if the reduced M-wave (reduced muscle activity) activity resulted in reduced muscle strength in ME/CFS as well. In a prior study, Jammes showed that reduced handgrip strength in ME/CFS was associated with a reduction in maximum energy production during exercise.

In this study, two groups of patients were found – one with normal EMG readings and one with abnormal EMG readings. People with abnormal M-wave readings had more symptoms and more post-exertional malaise after the exercise compared to the ME/CFS patients with normal M-wave activity.

Plus, reduced handgrip strength was associated with reduced M-wave activity; i.e. with reduced activation of ME/CFS patients’ muscles in a large subset of patients. With this new study, Jammes was able to potentially link a reduction in the ME/CFS patients’ ability to produce force with a reduced ability to activate the muscles. Both Fulle and Jammes believe that damage to the muscle membranes is caused by increased levels of reactive oxygen species (ROS); i.e. free radicals.

Oxidative Stress and Membrane Damage

High levels of oxidative stress are perhaps the most consistent finding in ME/CFS. Every study that I know of that has looked for it has found both increased levels of oxidative stress and reduced levels of antioxidants. They are particularly interesting because the mitochondria produce so many of them and damaged mitochondria can produce even more.

Paul and Lemle, for instance, propose that an infection-triggered mitochondrial breakdown in long COVID and ME/CFS disrupts the redox (oxidative stress) balance, and produces massive levels of free radicals, which then feed an inflammatory process that impacts the blood vessels, in particular, but also the brain, the muscles, etc.

Over time, in diseases like ME/CFS with reduced antioxidant levels, they believe that a positive feedback loop is established: the high levels of mitochondrial-produced reactive oxygen species (oxygen-based free radicals) damage the endothelial cells lining the blood vessels – producing inflammation – which produces more free radicals – which causes more damage, etc. Essentially a fire gets lit that never gets put out.

Could a Free Radical Explosion Be Causing ME/CFS and Long COVID?

Membrane Damage (Again)

Cell membranes are like catnip to oxidative stress or free radicals. In their attempt to rebalance their energy state, free radicals love to rip holes in cellular membranes. High levels of oxidative stress, then, go hand in hand with cellular membrane damage.

The membranes that cover our cells protect them from pathogens, toxins, and free radicals, and allow them to communicate with other cells, presenting the conduit through which all signals to the cells must pass. If the signal can’t get through to the cell, it can’t react to anything properly. It might as well be inert.

Recent ME/CFS studies have raised the question of whether serious damage to the cell membranes has occurred in ME/CFS. Fulle and Jammes have been raising the same question with regard to the membranes surrounding the muscles in ME/CFS for about 20 years.

Perhaps because Fulle and Jammes are lone wolves working in countries without a history of much ME/CFS research, their studies don’t seem to have received much attention.

With their 2021 hypothesis, “Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Wirth and Scheibenbogen, though, made ionic muscle pump problems a central part of their hypothesis which added B2AdR receptors, the sodium-calcium exchanger and the sodium proton exchanger to the mix.

On the long COVID side, muscle-mitochondrial problems have already shown up.

Long-COVID Exercise Study Points to Mitochondrial Dysfunction and Twitchy Muscles

An Explosion of Muscle Studies

Fulle and Jammes are getting some help.  The Open Medicine Foundation is leading the pack with two major muscle studies from David Systrom and Wenzhong Xiao.

One consists of a deep, deep dive (genomics, proteomics, metabolomics, phospho-proteomics, ultrastructural analysis, mitobiogenetic markers) into muscle samples from ME/CFS patients.

The next will take muscle samples before and after a two-day CPET exercise test and, among other things, assess levels of citrate synthase (which Systrom has found depleted in ME/CFS before), gene expression, metabolites and proteins in the muscles- – and mitochondrial functioning, cytokine, gene expression, metabolites and proteins in the blood.

  • Interested in participating in an Open Medicine Foundation study? Sign up here.

Plus – thanks to Dakota – we know that Paul Hwang of NHLBI and Avindra Nath are continuing to collaborate on their muscle cell findings. Then there’s Rob Wust’s Solve M.E. Ramsay award that’s examining muscle biopsies before and after exercise as well.

Conclusion

Through a series of sometimes small studies, Jammes and Fulle have put together a nice picture of neuromuscular dysfunction in ME/CFS driven by high levels of oxidative stress. Not only have they found direct evidence of damaged membranes (as well as DNA), but they’ve been able to show that people with reduced muscle activity – thought to be the result of damaged membranes – experience more PEM, have more symptoms, and can produce less force.

Jammes’s studies suggest that the heat shock proteins that protect muscle cells as they become fatigued are reduced. Fulle’s muscle tissue gene expression study highlighted a slew of genes involved in the usual suspects – energy production, mitochondria, oxidative stress, etc. – that were altered in ME/CFS. Plus, her study suggests that the muscle tissues have been altered and more fast-twitch, quick-fatiguing muscle fibers are present.

Because about half of the patients had reduced muscle excitability, while the other half did not, cannot explain all the exercise intolerance or the PEM that’s present in everyone with ME/CFS.

The Open Medicine Foundations’ deep dive into muscle cells and exercise plus the NIH’s continuing research into ME/CFS muscles and the recent Ramsay Award should tell us much about this potentially critical area of ME/CFS research.

 

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