Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles

Tom Aschman; Emanuel Wyler; Oliver Baum; Andreas Hentschel; Rebekka Rust; Franziska Legler; Corinna Preusse; Lil Meyer-Arndt; Ivana Büttnerova; Alexandra Förster; Derya Cengiz; Luiz Gustavo Teixeira Alves; Julia Schneider; Claudia Kedor; Judith Bellmann-Strobl; Aminaa Sanchin; Hans-Hilmar Goebel; Markus Landthaler; Victor Corman; Andreas Roos; Frank L Heppner; Helena Radbruch; Friedemann Paul; Carmen Scheibenbogen; Nora F Dengler; Werner Stenzel

doi:10.1186/s40478-023-01662-2

Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles

Acta Neuropathol Commun. 2023 Dec 8;11(1):193. doi: 10.1186/s40478-023-01662-2.

Authors

Tom Aschman¹, Emanuel Wyler², Oliver Baum³, Andreas Hentschel⁴, Rebekka Rust^{5

6}, Franziska Legler⁵, Corinna Preusse^{7

8}, Lil Meyer-Arndt⁵, Ivana Büttnerova⁹, Alexandra Förster⁷, Derya Cengiz¹⁰, Luiz Gustavo Teixeira Alves², Julia Schneider¹¹, Claudia Kedor⁶, Judith Bellmann-Strobl⁵, Aminaa Sanchin¹², Hans-Hilmar Goebel^{7

13}, Markus Landthaler^{2

14}, Victor Corman¹¹, Andreas Roos^{15

16}, Frank L Heppner^{7

17

18}, Helena Radbruch⁷, Friedemann Paul^{5

19}, Carmen Scheibenbogen⁶, Nora F Dengler^#¹², Werner Stenzel^#⁷

Affiliations

¹ Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany. tom.aschman@charite.de.
² Max Delbrück Center for Molecular Medicine, Berlin Institute for Medical Systems Biology, Berlin, Germany.
³ Institute of Physiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
⁴ Leibniz-Institut Für Analytische Wissenschaften - ISAS - E.V, Dortmund, Germany.
⁵ Experimental and Clinical Research Center and NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
⁶ Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
⁷ Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
⁸ Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
⁹ Department of Autoimmune Diagnostics, Labor Berlin-Charité Vivantes GmbH, Berlin, Germany.
¹⁰ Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
¹¹ Institute of Virology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
¹² Department of Neurosurgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
¹³ Department of Neuropathology, Universitätsmedizin Mainz, Mainz, Germany.
¹⁴ Institute for Biology, Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁵ Department of Pediatric Neurology, Faculty of Medicine, University Children's Hospital, University of Duisburg-Essen, Essen, Germany.
¹⁶ Department of Neurology Bergmannsheil, Heimer-Institut Für Muskelforschung am Bergmannsheil, Bochum, Germany.
¹⁷ Cluster of Excellence, NeuroCure, Berlin, Germany.
¹⁸ German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany.
¹⁹ Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

^# Contributed equally.

Abstract

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also in many cases of post-infectious syndromes, colloquially referred to as "long COVID". Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169⁺ macrophages. SARS-CoV-2 RNA could not be detected in the muscle tissues. In addition, complement system related proteins were more abundant in the serum of patients with PCS, matching observations on the transcriptomic level in the muscle tissue. We hypothesize that the initial viral infection may have caused immune-mediated structural changes of the microvasculature, potentially explaining the exercise-dependent fatigue and muscle pain.

Keywords: Basement membrane thickening; ME/CFS; Microangiopathy; Post-COVID syndrome; Post-acute sequelae of COVID-19 (PASC); Post-infectious syndrome; SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19*
Capillaries*
Fatigue
Humans
Muscle, Skeletal
SARS-CoV-2

Abstract

Publication types

MeSH terms

Grants and funding