Getting their due – the muscles in ME/CFS

Cort Johnson from the Health Rising blog explores some of the muscle abnormalities identified in recent ME/CFS research, and how these may contribute to the symptoms of the disease. This includes a discussion of Rob Wüst’s recent long-COVID study, which Dr Wüst is following up with a study in ME/CFS, funded by ME Research UK and to be announced later this week.

It’s hard to believe that the muscles don’t play a major role in this exertionally challenged disease. Two-day exercise studies indicate that engaging in even short bouts of intensive exercise one day will impair the ability of most ME/CFS patients to produce energy the next day. Furthermore, invasive exercise studies indicate that normal levels of oxygen – the lifeblood of energy production – aren’t getting into the muscles of many ME/CFS patients.

It seems that the muscles MUST be involved. The question is, how? Have they been damaged? Are they not getting enough oxygen? Or is something happening outside of the muscles that’s preventing them from working properly?

Yves Jammes in France and Sopia Fulle in Italy have been exploring the muscles in ME/CFS for about twenty years. First, they looked at electrical activity to see if the muscles were being activated enough. Finding evidence of reduced electrical activity (M-waves) in ME/CFS, they then turned their attention to the muscle membranes.

Muscle action begins when the muscle membranes send a message to the muscles to contract. Jammes, though, found enough evidence of muscle membrane problems to call ME/CFS a “systemic disorder of muscle membrane excitability“. 

Looking for a cause, the researchers found increased levels of oxidative stress (free radicals) and reduced levels of the protective heat shock proteins.

However, things really picked up recently with the emergence of ME/CFS’s kissing cousin, long COVID, which evidence indicates is similar to ME/CFS.

One long COVID study found that altered muscle fibre types and difficulty activating the clean, efficient aerobic energy system resulted in a dependence on anaerobic energy production and ultimately hyperventilation.

Noting that similar findings are present in ME/CFS, the authors proposed that the enzymes driving mitochondrial activity were probably depleted, and that the skeletal muscles (not the heart) were undergoing a process akin to that seen in heart failure. Their idea seemed to jibe with the conclusions of another paper – “Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome” – which proposed that mitochondrial problems and oxidative stressors were causing ME/CFS patients’ muscles to age more rapidly than normal.

These findings set the stage for Rob Wüst’s remarkable long-COVID study – “Muscle abnormalities worsen after post-exertional malaise in long COVID“.

Wüst, an exercise physiologist and mitochondrial researcher, did something simple but profound. He took muscle biopsies from long-COVID patients and recovered COVID-19 controls, exercised the participants to exhaustion, and then took another round of muscle biopsies and compared them.

Besides the expected reduction in maximum energy output found in the long-COVID patients, Wüst found that their muscles were not taking up less oxygen (read energy) than normal.

Digging deep into muscles, Wüst found a higher proportion of highly fatiguable type-II or fast-twitch fibres in the long-COVID patients. These muscle fibres produce energy anaerobically and help with short-duration bursts of energy, but provide little endurance. (A 2009 ME/CFS study also found increased levels of these “fatigue-prone, energetically expensive” muscle fibres.)

Wüst demonstrated that intense exercise may be harming the muscle fibres themselves when he showed that 80% of long-COVID patients displayed atrophied muscle fibres after exercise (up from 50% before exercise) and a third displayed necrotic or dead muscle fibres. That suggested exercise was prompting immune cells to invade the muscles – something rarely seen in healthy muscles – and therefore that exercise may be triggering an autoimmune response that’s attacking the muscles.

Wüst next found that the activity of a key mitochondrial enzyme called succinate dehydrogenase (SDH) decreased in the long-COVID patients. It was increased in the healthy controls. Since SDH is the only enzyme to participate in the two major parts (the electron transport chain and TCA/Krebs cycle) of aerobic energy production, an exercise-induced reduction of SDH activity would surely seem to make it more difficult to exert oneself.

You can read a more detailed description of these results on the Health Rising blog.

Next, the stars shone on the ME/CFS community when an unlikely train of events produced what may be a major finding. Paul Hwang at the NIH was studying cancer in a family when he came across a family member who had become steadily more fatigued after coming down with infectious mononucleosis.

Her muscles exhibited very high levels of a protein called WASF3 which Hwang knew little about. Checking the literature, though, Hwang – who also knew nothing about ME/CFS – found a reference to WASF3 in an obscure 2011 ME/CFS study.

Hwang and his team began a full-court press on their findings. They found lower oxygen consumption (energy production), a 34% drop in the levels of the cytochrome oxidase enzyme in the mitochondria, and unusually prolonged recovery times after exercise.

Returning the WASF3 protein levels to normal in mice resulted in increased energy. Digging into WASF3 like no one had ever dug into it before, they were able to show that increased levels of WASF3 are associated with reduced mitochondrial energy production.

Heading upstream they found that levels of WASF3’s regulator (BiP) – located in the endoplasmic reticulum (ER) – were even more altered than WASF3 was. They concluded that endoplasmic reticulum stress triggered high WASF3 levels in ME/CFS, which, in turn, were reducing energy production.

This provided, perhaps for the first time, “a molecular explanation for the energy deficiency symptoms of exercise intolerance and postexertional malaise… in chronic fatigue”. The molecular part is vital because finding the molecular underpinnings of ME/CFS will allow researchers to target them with drugs – which is precisely what Hwang now wants to do with ME/CFS.

The increasing findings around the muscles in ME/CFS have not gone without notice. Suddenly, ME/CFS is awash with muscle studies! Two are underway at the Open Medicine Foundation-funded Harvard Collaborative ME/CFS Center, and the Solve ME Initiative is funding a third by none other than Rob Wüst. In addition, Paul Hwang and Avindra Nath at the NIH are continuing to extend the WASF3/muscle cell findings.

[To these we can also add Rob Wüst’s forthcoming ME Research UK-funded study, to be announced later this week.]

The muscles in ME/CFS are finally starting to get their due.

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