Should we be careful with exercise in post-exertional malaise after long COVID?

arising from B. Appelman et al. Nature Communications https://doi.org/10.1038/s41467-023-44432-3 (2024)

Post-exertional malaise after COVID-19 infection is a debilitating postviral condition. We applaud the work of Appelman et al.¹ addressing the important questions on how long COVID develops and how to treat this condition. From our experience with mitochondrial diseases and training strategies in neuromuscular diseases, we would like to comment on the findings and conclusions drawn in this study. The suggestion that strenuous exercise increases symptoms of myalgia and exercise intolerance is, in our opinion, not specific for long COVID. In addition, it could now be interpreted that exercise should be avoided. However, the opposite is true as we will elaborate.

Establishing lower maximal (or peak) oxygen consumption in patients with long COVID is important and a confirmation of previous work in long COVID and other post-viral symptoms^2,3,4,5. Besides a lower maximal oxygen consumption, Appelman et al. have found a higher proportion of glycolytic fibers, lower CSA of type I fibers, lower peak power output, lower OXPHOS capacity, lower citrate to lactate ratio, and lower concentration of creatine. The combination of these (latter) findings points in the direction of deconditioning in addition to a direct post viral effect. Decrease in mitochondrial content has also been found in patients with chronic fatigue syndrome compared to healthy controls⁶, and mechanisms of post-viral loss of mitochondrial content could be similar.

Authors state that the examined long COVID patients were physically active with an average of 4000 steps a day, which equates to about 3.2 km or between 30 and 45 min of daily walking, depending on speed. However, the number of daily steps was significantly lower, around 30–40%, compared to the control group used in this study. This difference in daily exercise is on top of their low aerobic capacity. Favorable mitochondrial adaptations in muscle can only be achieved if training is performed at a sufficient frequency, intensity, and duration for an adequate length of time⁷.

Appelman et al. state that severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen one day after strenuous exercise. According to our experience such findings cannot arise in just one day. Muscle damage after strenuous exercise starts with sarcolemmal lysis and destruction of the basal lamina resulting in fiber necrosis with concomitant endomysial cell infiltrates to remove cell debris. Cytokines accelerate the inflammatory response and induce myoblast proliferation. Satellite cells become activated, proliferate, and differentiate into multinucleated myotubes and eventually into regenerated myofibers. Active muscle degeneration and inflammation occur in the first few days post-injury, whereas muscle regeneration usually occurs seven to ten days after injury^8,9. Muscle atrophy occurs as the rate of protein degradation exceeds that of protein synthesis¹⁰. The development of atrophied and regenerative cells in the muscle takes at least a few days since the half-life of contractile proteins is 3–4 days¹¹. Therefore, it is unlikely that the incremental test itself cause post-exertional malaise in long-term COVID, based on these histological findings.

Mild histopathological abnormalities are often present in healthy control biopsies¹². After training, muscle fiber turnover and regeneration are part of normal physiology¹³. There is no correlation between the abnormalities on histology and perceived myalgia and exercise intolerance. More importantly, normal muscle contains a considerable number of macrophages and T-lymphocytes¹⁴. The authors suggested a direct link between the found muscle abnormalities, perceived myalgia, and exercise intolerance. The current study lacks a control group with similar fitness levels, which limits the interpretations of findings.

In conclusion, the message that intensive exercise can damage the muscle in long COVID is, in our view, not demonstrated. Additionally, it can be interpreted by patients that exercise with concomitant muscle fatigue and myalgia might cause muscle damage, resulting in patients not exercising at all. Training at the correct intensity, where most time is spent at maximal aerobic metabolism, increases mitochondrial density and lactate membrane transporters and will improve oxidative capacity, also in long COVID patients^15,16,17. Many patients have difficulty adjusting their intensity of physical activity and training to the new level of fitness.

We underline that research on the cause of decreased aerobic capacity in long-COVID and similar post-viral conditions is needed. Better therapies should become available. Improvements in muscle fitness can act as therapy in long COVID, and supervised training at different volumes and intensities should be tested at specialized centers according to established guidelines and compared to participants of equal fitness level.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.