Fatigue and Post-Exertional Malaise Part 2

Validating Research on Fatigue and PEM by Professor Robert Wüst and Colleagues

In March 2024, I created a short informational video summarizing a paper published by Dutch researchers from Professor Rob Wüst’s lab (Appelman et al., 2024). They investigated whether the biology of fatigue (defined as impaired exercise capacity) differs from that of post-exertional malaise (defined as post-exercise changes to the muscle) in people with long COVID.

You can watch that video on my Tip of the Month page by scrolling down to March 2024. The paper I discussed, Muscle abnormalities worsen after post-exertional malaise in long COVID, is freely available online. It is pretty technical and not an easy read, even for me. Here is a brief summary of the key findings.

Wüst and colleagues conducted a very detailed study of muscle-related impairments in people diagnosed with long COVID who experienced fatigue and PEM.

• They assessed fatigue by analyzing muscle cell structure and function at baseline before exertion.
• They assessed PEM by noting new abnormalities that developed after the bout of exercise, which differed from those in the control group.

The research included 25 long COVID patients and 21 age- and sex-matched healthy controls who had recovered from mild SARS-CoV-2 infection. The long COVID group was not bedridden. They had an average step count of 4000 steps/day, similar to an average person with FM or moderately severe ME.

The Wüst study showed that fatigue and PEM are not the same.

• Before exercise, participants with long COVID exhibited abnormalities in muscle structure, changes in mitochondrial function and abnormalities in immune function, providing objective evidence of fatigue in people with long COVID.
• In the long COVID group, there was an increase in glycolytic (anaerobic) metabolism and a change in muscle fiber ratios. Less energy was being produced, and the muscles fatigued more quickly.
• During exercise, the subjects with long COVID achieved lower maximal oxygen uptake (VO2 max) and peak power output than those who had recovered from acute COVID infection.
• Subjects with long COVID achieved lower ventilatory function during exercise. This means they moved less air in and out of their lungs, and the skeletal muscle extracted less oxygen during exercise as measured by near-infrared spectroscopy. This is evidence of fatigue—a reduced capacity to perform exercise.
• PEM is measured by what happens after exercise. They found evidence that the mitochondria were making even less energy after exercise than before.
• They found evidence of damage to the muscle cells after exercise and evidence of increased muscle repair.
• There was an accumulation of a misfolded protein called amyloid after exercise in the long COVID group, all of whom experienced PEM. Amyloid prevents cells from functioning optimally.
• There were differences in the immune response to exercise between subjects with long COVID and those who had recovered.
• They tested two common theories of long COVID. It has been suggested that long COVID is caused by the persistence of the SARS-CoV-2 virus or the spike protein. Although this has been shown in other studies, there was no evidence of viral persistence in the muscle cells of these subjects.
• Another popular theory is that fatigue is caused by decreased blood flow to tissues due to microclots in the tiny blood vessels. There was no evidence of microclots in the small vessels providing blood to the muscle.

Conclusions

In people with long COVID, both fatigue and post-exertional malaise are pathological conditions. Meaningful, measurable abnormalities are found in the muscles at baseline—abnormalities that prevent people from full function. And even more abnormalities are found after a bout of exercise—abnormalities which may be related to the worsening of symptoms or “crash” people with PEM experience with exertion.

If you experience fatigue or PEM, your symptoms are not in your head; they are, at least in part, in your muscles.

It is important to note that other body organs impacted by long COVID, such as orthostatic intolerance, unrefreshing sleep and brain fog, were not measured. These other organs/body systems may show similar or different abnormalities to those found in the muscles. At the risk of stating a cliché, more research is needed.

If you are interested in learning more about potential causes of PEM and the best management of fatigue and PEM, keep reading. In Part 3 of this 4-part blog post, I discuss some of the leading ideas of what causes PEM.