A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

Original languageEnglish
Article number17
Pages (from-to)17
JournalNature communications
Issue number1
Publication statusPublished - 4 Jan 2024


  • COVID-19/complications
  • Case-Control Studies
  • Fatigue/etiology
  • Humans
  • Muscle, Skeletal
  • Musculoskeletal Abnormalities
  • Pain
  • Plaque, Amyloid
  • Post-Acute COVID-19 Syndrome
  • SARS-CoV-2

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