Blog: What changes in skeletal muscles and blood of people with ME/CFS and post-exertional malaise?

Typical symptoms experienced by ME/CFS patients, like fatigue and muscle ache, generally get worse with physical exertion. This is known as post-exertional malaise (PEM). The cause of PEM is still unknown.  ‘It is likely that something changes in the skeletal muscles, the blood and possibly also in the response of immune cells', says muscular physiologist Rob Wüst of Vrije Universiteit Amsterdam. More knowledge of what happens could point researchers towards a suitable treatment. 

'We think that muscle function changes in people with ME/CFS. People with cardiopulmonary disease also experience changes in their skeletal muscles and metabolism. Fatigue and loss of concentration after exertion are also known symptoms of these diseases, but they are not as extreme as what we see with ME/CFS. It could be that not all ME/CFS patients have these symptoms to the same degree, and that different substances also play a role in PEM. So I want to discover which substances in the skeletal muscles and blood cause the exhaustion, and which are specific to PEM.' Wüst has been awarded a grant for his Adaptations in the skeletal muscle and blood during post-exertional malaise in patients with ME/CFS project to enable him to research this.

'Are there substances in the blood that cause severe fatigue in PEM, or in the skeletal muscles? To find out, we need to collect information about the skeletal muscles and blood of patients. We also need access to the data of enough healthy people so we can compare the appearance of their muscles (the skeletal muscle phenotype) and the composition of their blood (blood phenotype) with the patients with ME/CFS. 

‘To include a large amount of data in the study, we’re using the biobank of the Dutch ME/CFS Cohort and Biobank (NMCB). Soon the NMCB will start recruiting patients and healthy people for the biobank. We’re also going to recruit patients and healthy individuals, and share our data with the biobank. We’ve already made a start, and have collected our first data from 25 patients with ME/CFS.'

‘To find out the cause of fatigue in ME/CFS, and PEM in particular, we’re asking patients to come in for a bike test. We’re using blood tests and muscle biopsies to investigate whether levels of certain substances in the blood are higher or lower after exertion. It can take a while before you can measure these substances, because PEM symptoms sometimes don’t appear until the next day, and we have to consider that. So we’re planning to ask patients with ME/CFS to come in for measurements a week before the bike test, the day of the test, and the day after. That will help us understand the mechanism that causes PEM.

'I realise that the bike test can be hard for patients with ME/CFS, and might cause more PEM symptoms. So we’ve drawn up a protocol in consultation with two patient representatives. With every patient, we always stop to consider if the goal of the study and a better understanding of the illness weighs up against the personal effort we’re asking of them. Whether it’s ethically responsible to ask this of people with ME/CFS? We don’t ask people who are seriously ill to take part in this kind of study.'

‘Since a viral infection may be the underlying cause of PEM, we also want to include post-COVID patients in the study. They, too, experience PEM symptoms after exertion. In a previous study by our group we found tiny clots – microclots – circulating in the blood of post-COVID patients. These patients also have decreased energy production, which is probably what causes their fatigue symptoms. We don’t know what role the microclots play, so we’re going to study this further, both in patients with ME/CFS and post-COVID, with our partner in South Africa. They are now analysing the blood collected from both the post-COVID patients and the first ME/CFS patients. Then we’ll look to see whether the number of microclots increases after exertion, and maybe see how big they are. What do these microclots do in patients with post-COVID or ME/CFS? We should have the first results after summer 2024.'

‘Besides the changes in the skeletal muscles and blood, we also expect to find a disrupted immune system in people with ME/CFS. Our colleagues in South Africa have found that the microclots in post-COVID patients contain substances that attack the body, which is also known as autoimmunity. There are also patterns of autoimmunity in the blood, but we don’t know how this is related to the changes in muscles. This might also be the case in people with ME/CFS, and we plan to investigate that now. We expect to be able to reduce the burden and improve quality of life once we know more about the role of the immune system in ME/CFS.'

`We hope, by analysing the patient data in the biobank, and from the bike test, to discover substances that might explain the restricted skeletal muscle function in ME/CFS patients. These substances, which we’ll hopefully find in moderately ill patients, might also be present in the blood of severely ill patients from the biobank. We can then compare the two groups, which will give us a starting point to look for molecules that might affect these substances. We also call these measurable molecules biomarkers. They tell us about the change in muscular function and the severity of the disease. 

‘Once we’ve found one or more of these biomarkers, there’s a hope of better diagnosis for people with ME/CFS and PEM. It will also help us to develop a suitable treatment more quickly, because the biomarkers tell us more about the cause of the symptoms. That could serve as a basis for finding a drug treatment. Above all, it will help decrease the burden of the disease.' 

‘My interest in ME/CFS comes from the COVID pandemic, actually. As a muscular physiologist, I have seen for myself that some people have not recovered properly from COVID. So I wanted to do something about that. We also had patients ask us directly to do more research on PEM in ME/CFS. So we carried on with that, which led to this study, which we can now do thanks to the ZonMw grant.'

For more information about the research project and the ZonMw ME/CFS research programme, please refer to the pages below.

• The project page
• The consortium website
• The programma page about the Research programme ME/CFS
• Our theme page about fatigue

Text: Ilse Bos, Photography: Robert Tjalondo, privite archive Rob Wüst