Fatigue and Post-Exertional Malaise Part 3

What Causes Post-Exertional Malaise?

In Part 1 of this four-part blog series, I described what it feels like to have disabling fatigue and post-exertional malaise (PEM). In part 2, I summarized some significant research findings that validate fatigue and PEM as distinct pathologic conditions, which differ from one another. In this part, I delve into some of the possible biological causes of PEM.

For those who haven’t read Part 2, the following are the key findings of the Wüst 2024 study:

• The group with long COVID has lower exercise capacity than the group who had recovered from acute SARS-CoV-2 infection. This impaired function was due to muscle impairment rather than cardiovascular dysfunction.
• Even before exercise, people with long COVID and PEM show abnormalities in muscle structure, changes in mitochondrial function and inflammatory changes. These objective findings suggest a biomedical cause of fatigue in people with long COVID.
• Metabolic disturbances, muscle damage and amyloid accumulation increased after exercise in the long COVID group. This suggests that the muscles of the long COVID/PEM group take longer to recover from activity. This is a cardinal sign of PEM.
• There was no evidence of viral persistence in the muscle.
• There was no evidence of micro-clots in the small vessels providing blood to the muscle.

So, What Does Cause Post-Exertional Malaise?

PEM is NOT Caused by Deconditioning

One of the earliest theories about the cause of PEM in ME/CFS and long COVID is that it is caused by deconditioning. That has been thoroughly debunked by numerous studies and researchers (Appelman et al., 2024; Wilshire, 2016). Nevertheless, many underinformed people, especially those connected with the insurance industry, continue to view exercise therapy as a treatment. So, it is useful to review some of the evidence against the deconditioning hypothesis:

• Many people with PEM maintain activity levels similar to those of healthy, sedentary individuals. This doesn’t say much for the activity levels of healthy people, but it shows that people with long COVID are pushing to stay active.
• The muscle abnormalities found in people with long COVID differ from those caused by bed rest or immobility.
• Aerobic impairments and PEM symptoms persist despite physical rehabilitation. In healthy, deconditioned people, increased activity leads to improved function.

Deconditioning, when it exists, is likely to be a result of prolonged illness and skeletal muscle dysfunction rather than a cause. It is also important to note that people with ME and long COVID develop PEM from cognitive and emotional activities; therefore, explanations of PEM based solely on muscle function are incomplete.

Note that it is very difficult to differentiate the causes and mechanisms of fatigue from those of PEM. The list of abnormalities in ME and long COVID is very long (Charlton et al., 2025; Komaroff & Lipkin, 2023). Some likely pertain to fatigue, and some to PEM. This is a brief summary of some of the most well-documented findings.

Possible Contributors to Post-Exertional Malaise

1. Impaired Energy Production

• Cellular energy production is consistently decreased in both long COVID and ME/CFS.
• This is related to increased glycolysis and less oxidative phosphorylation as the primary means of energy generation.
• Mitochondria in ME and long COVID are smaller, more fragmented and less efficient.
• Muscles in long COVID contain more easily fatiguing muscle fibers than in healthy individuals. This makes it harder to sustain activities over time.

2. Problems with blood flow and blood oxygen

• The tissues take up less oxygen.
• In his book, Understanding ME/CFS & Strategies for Healing, Patrick Ussher shows photos of his blood before and after a medical treatment called apheresis in which the blood is filtered and cleansed. After his blood was filtered, there was a remarkable change in color, from almost black to blood red.
• Apheresis is being studied at Charité Hospital in Berlin, Germany, by Professors Carmen Scheibenbogen and Klaus Wirth. You can read more about their model of ME/CFS and a potential drug treatment in Patrick’s May 2025 guest blog.
• Although many believe tiny micro-clots blocking the blood vessels contribute to fatigue and PEM, the evidence for this remains inconclusive.

3. Inflammation and Autoimmunity

• People with ME/CFS and long COVID patients have dysregulated immune systems that are often overactive but under-effective in fighting off infections.
• A subgroup of people with PEM has autoantibodies against β2-adrenergic and other receptors that control the autonomic nervous system.
• When present, these antibodies impact blood flow, energy production during exercise and the function of nerves and muscles.
• Autoantibodies are causal in diseases such as myasthenia gravis and myositis, conditions in which exercise intolerance and muscle weakness are prevalent.

4. Brain Involvement

• People with ME, CFS and long COVID patients report brain symptoms like problems thinking quickly and clearly, chronic pain, unrefreshing sleep and low or irritable mood.
• It is harder to study the brain—you can’t do a brain biopsy in a living person, so we rely on advanced imaging, like functional MRI, to try to figure out what is going on in the brain. fMRI and regular MRI findings repeatedly show changes in the function and structure of the brain.
• When immune overactivation occurs in the brain, it is called “neuroinflammation,” and it is very possible that this contributes to fatigue and PEM.
• When brain blood flow is measured, it is consistently found to decrease in ME and long COVID. Decreased blood flow is associated with decreased function.

This was a very brief summary of some of the most interesting research findings in people who experience PEM. We don’t know if any are causal, nor which are upstream and worth targeting with treatments. Go to Part 4, the final section of this blog series, to read about emerging treatments.

References

Appelman, B., Charlton, B. T., Goulding, R. P., Kerkhoff, T. J., Breedveld, E. A., Noort, W., . . . Wüst, R. C. I. (2024). Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature communications, 15(1), 17. doi:10.1038/s41467-023-44432-3

Charlton, B. T., Goulding, R. P., Jaspers, R. T., Appelman, B., van Vugt, M., & Wüst, R. C. I. (2025). Skeletal muscle adaptations and post-exertional malaise in long COVID. Trends in Endocrinology & Metabolism. doi:10.1016/j.tem.2024.11.008

Komaroff, A. L., & Lipkin, W. I. (2023). ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature. Frontiers in Medicine, 10, 1187163. doi:https://dx.doi.org/10.3389/fmed.2023.1187163

Wilshire, C. K., T.; Alem Matthees & Simon McGrath  (2016). Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial,. Fatigue: Biomedicine, Health & Behavior, 5(1), 43–56. doi: 10.1080/21641846.2017.1259724