Post-Exertional Malaise in Long COVID Linked to Muscle, Metabolic Abnormalities


Myopathy, with metabolic disturbances and amyloid deposits, is discovered in persons with Long COVID who experience post-exertional malaise.

Persons with Long COVID who experience worsened fatigue and muscular pain after exercise are ill-served by admonishment of "no pain, no gain," given new findings that link their condition to skeletal muscle myopathy characterized by metabolic disturbances.

In an interview with National Public Radio, study co-author Braeden Charlton, MSc, PhD Candidate, Faculty of Behavioural and Movement Sciences, Physiology, Vrije Universiteit Amsterdam, commented, "This is a very real disease.We see this at basically every parameter that we measure.1

"It's not just soreness, Charlton emphasized, "for a lot of people, its completely debilitating for days to weeks."

Investigators assessed physiological changes after exercise in 25 persons with Long-COVID and in 21 healthy controls who had recovered from COVID without sequelae, in a longitudinal case control study.2 Through blood samples and skeletal muscle biopsies before and after maximal exercise, they sought to distinguish pathophysiologic processes of the post-exertional malaise from exercise-related physiologic changes in those without ongoing symptoms.

"We show that skeletal muscle structure is associated with a lower exercise capacity in patients and that local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-deposits in skeletal muscles of patients with Long COVID worsen after induction of post-exertional malaise," declare lead author Brent Appleman, MD, PhD, Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Amsterdam, the Netherlands, and colleagues.

All participants underwent cardiopulmonary exercise on a cycle ergometer, and those with long COVID demonstrated substantially lower maximal oxygen intake (VO2max) and peak power output, albeit with inter-patient heterogeneity. Post-exertion malaise was experienced by all those with Long COVID, with such symptoms as muscle pain, greater severity of fatigue and cognitive symptoms up to 7 days after the maximal exercise test.

The cardiovascular system was not found to be compromised, however, suggesting other processes underlying the results. From the muscle biopsies, the investigators found a high proportion of highly-fatigable glycolytic fibers and lower mitochondrial function in those with long COVID.

Mitochondrial respiration and metabolomic signatures from the biopsies and blood samples revealed, among other findings, that the tricarboxylic acid (TCA) cycle metabolites were lower in skeletal muscle and blood in those with long COVID. Succinate dehydrogenase (SDH) activity, a marker for mitochondrial content correlated with VO2max in healthy controls but not in those with Long COVID.

What You Need to Know

The study reveals a connection between post-exertional malaise in long COVID patients and skeletal muscle myopathy.

Post-exertional malaise in long COVID is not merely soreness but can be completely debilitating for days to weeks.

Long COVID patients demonstrated lower exercise capacity, maximal oxygen intake (VO2max), and peak power output compared to healthy controls

The investigators suggest that the combination of a reduced maximal mitochondrial respiration and decreased mitochondrial content are part of the pathophysiology of post-exertional malaise.

"The mitochondria are operating at a severely reduced capacity compared to healthy people," Chariton commented in the NPR interview.

The investigators found greater concentrations of amyloid-containing deposits in the skeletal muscle of those with long COVID at baseline, although these increased in both groups in response to the exercise test.The deposits were not found to block local perfusion, as has been postulated, and so were not linked to local tissue hypoxia.

"The underlying reason for the increased intramuscular accumulation of amyloid-containing deposits during post-exertional malaise remains elusive," the investigators observe.

Appleman and colleagues note that theirs is an observational study, and so does not establish causality.They also point out, however, that "this is the first study providing evidence of severe tissue damage upon acute exercise in long COVID patients."


1. Stone W. A discovery in the muscles of Long COVID patients may explain exercise troubles. National Public Radio, January 13, 2004. Accessed January 13, 2024.

2.Appelman B, Charlton BT, Goulding RP, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun 2024; 15:17. Published online Jan 4.doi: Accessed January 13, 2024.

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