Explaining Fatigue and Post-Exertional Malaise in Long COVID and ME/CFS: From Skeletal Muscle To Exercise Immunology

The SARS-CoV-2 viral outbreak in 2020 resulted in a record number of global hospitalizations and deaths. Although most people recover from an initial COVID infection within 3 months, around 10% of people have symptoms that do not improve after 3 months, which is called long COVID. Other viruses and bacterial infections can also result in long-term symptoms, which is known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

One of the most common symptoms of long COVID or ME/CFS is post-exertional malaise, which is the worsening of symptoms or development of new symptoms after physical, mental or emotional stress. This can lead to patients leading less physically active lifestyles. Physical activity is known to be beneficial for overall health and wellbeing, mostly by increasing exercise capacity, which is a significant predictor in long-term health. Physical inactivity.

It is thought that many symptoms of long COVID and ME/CFS can be explained by lower physical activity of patients. However, people who are less physically active don’t experience post-exertional malaise, implying there are disease-specific changes. Many of the benefits that come from exercise come from a persons ability to adapt to an exercise session. Usually, exercise will create a short energy deficit, which then may result in small amounts of muscle damage. This then triggers a short-lived immune response, led first by neutrophils and macrophages, which result in activation of fibroadipogenic progenitor cells (FAP cells) and satellite cells (muscle stem cells). FAP cells and satellite cells communicate to repair damage to the muscle itself, while immune cells clear debris surrounding the muscle. In healthy situations, this creates a stronger, more resilient muscle. It is unknown whether these responses are still seen in long COVID or ME/CFS. The goal of this thesis then to 1) understand muscle changes in patients with long COVID and ME/CFS, 2) to better understand how these changes may relate to PEM, 3) to understand whether the muscle changes in patients are a result of physical inactivity.

Within the thesis, I find that patients with long COVID and ME/CFS have specific patterns of skeletal muscle that separate them from healthy individuals. This is highlighted by more fast-twitch fibre types, slow-twitch muscle atrophy, lower mitochondrial respiration that is separate from just mitochondrial loss, less metabolites related to oxidative capacity and antioxidation, less lipids that are required for cell membrane maintenance, and lower amounts of satellite cells and FAP cells.

Beyond this, I find that ME/CFS can be distinguished from long COVID by less capillaries, less slow-twitch fibres, less local immune cells, and lower amounts of several essential amino acids. As well, I find evidence that physical inactivity alone cannot explain long COVID and ME/CFS symptoms. Where all of long COVID, ME/CFS, and physical inactivity have lower whole-body aerobic capacity, physical inactivity causes a decrease in muscle fibre size, loss of mitochondria, increases in muscle lipotoxic lipids, and decreases in metabolites related to carnitine metabolism. These changes are not seen in either long COVID nor ME/CFS, and support the idea that long COVID and ME/CFS have disease specific muscle changes.

Overall, I find that the reduced whole-body capacity of long COVID and ME/CFS patients is not cause by physical inactivity, and is defined by reduced muscle oxidative ability. The lower amounts of local cells that would normally support exercise and damage responses are lower in both long COVID and ME/CFS, which partially explains the occurrence of PEM. This also suggests that patients experiencing PEM should not undertake normal rehabilitation, however it might be that more individually tailored, and severely monitored approaches may still be beneficial.