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News Medical: Long COVID’s hidden toll: How does post-exertional malaise affect skeletal muscles?

In a recent study published in Nature Communications, researchers investigate the pathophysiology of post-exertional malaise (PEM) in long coronavirus disease 2019 (COVID-19) patients, focusing on skeletal muscle changes, exercise capacity, metabolic disturbances, and tissue alterations.

By Vijay Kumar Malesu | 08 January 2023



The present study was conducted at the Amsterdam University Medical Centers (UMC) and Faculty of Behavioral and Movement Sciences from Vrije Universiteit Amsterdam. Participants included long COVID patients and healthy controls, with the former diagnosed based on specific criteria, including PEM.

The research methodology included four visits in two weeks, during which participants were subjected to a maximal incremental ramp exercise test to induce PEM. Skeletal muscle biopsies were obtained before and after the exercise, in addition to venous blood samples obtained at each visit. Near-infrared spectroscopy (NIRS) was used to evaluate the extent of oxygenation and saturation within muscles, with participants wearing an accelerometer for measuring physical activity levels on a daily basis during this period.

Skeletal muscle mitochondrial function was assessed using permeabilized fiber respirometry. Immunohistochemistry was also used to evaluate muscle fiber morphology, the presence of amyloid-containing deposits, and signs of pathology.


Significantly reduced exercise capacity was observed in long COVID patients that was not associated with the cardiovascular system but poorer ventilatory function during exercise and peripheral skeletal muscle impairments. These patients had a lower maximal oxygen pulse, gas exchange threshold, and peripheral oxygen extraction, indicative of skeletal muscle issues. There was no evidence of submaximal effort affecting these results, as the proportion of participants reaching a plateau in oxygen uptake was similar across groups.

The progression of PEM among long COVID patients who exhibited higher muscle pain, tiredness, and cognitive symptoms after maximal exercise was also assessed. Notably, this condition developed despite the different exercise capacities of each study participant.

Metabolic and mitochondrial dysfunctions were explored to determine their possible involvement in this condition. To this end, these dysfunctions were found to be related to the pathophysiology of PEM.

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