 Physical activity and long COVID fatigue Eur J Transl Myol 33 (3) 11804, 2023 doi: 10.4081/ejtm.2023.11804 - 1 - Comments on: Effect of physical activity on long COVID fatigue Francesco Coscia (1), Ester Sara Di Filippo (2,3), Paola Virginia Gigliotti (4), Giorgio Fanò-Illic (3,5,6) (1) Sports Medicine Service of the San Candido-Innichen and Brunico-Bruneck Hospitals, Bolzano-Bozen, San Candido, Italy; (2) Department of Neuroscience Imaging and Clinical Sciences, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy; (3) IIM-Interuniversity Institute of Myology, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy; (4) Laboratory of Sport Physiology San Candido-Innichen, University of Perugia, San Candido, Italy; (5) Campus of Free University of Alcatraz, Free University of Alcatraz, Santa Cristina di Gubbio, Gubbio, Italy; (6) A&C M-C Foundation for Translational Myology, Padova, Italy. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Abstract The authors of the Comments on: Effect of physical activity on long COVID fatigue by Daungsupawong F. and Wiwanitkit V. (2023) have highlighted certain aspects of future research that need to be considered before any conclusions can be drawn regarding the effect of previous physical activity and/or fitness on the course of long-COVID. We can only agree with this need, although we hope that the effects of SARS-CoV-2 infection will become less and less burdensome to manage. As we hypothesise in the last part of the article by Coscia et al. (2023), we think it is crucial to identify the molecular mechanism underlying the atrophic effect (if any) of the described disease states, which could originate from a local inflammatory storm induced by Spike binding to the ACE-2 receptor in muscle. When studies on muscle from patients will be available in sufficient numbers, we will be able to try to answer the still open questions. Key Words: Effect; physical activity; long COVID; fatigue. Eur J Transl Myol 33 (3) 11804, 2023 doi: 10.4081/ejtm.2023.11804 The authors of the Comments on: Effect of physical activity on long COVID fatigue by Daungsupawong F. and Wiwanitkit V.1 have highlighted certain aspects of future research that need to be considered before any conclusions can be drawn regarding the effect of previous physical activity and/or fitness on the course of long- COVID (comorbidities, vaccinations). We can only agree with this need, although we hope that the effects of SARS-CoV-2 infection will become less and less burdensome to manage in the near future. However, muscle fatigue that is not relieved by rest is a common symptom of many established or questionable viral diseases.2 The use of the exercise approach to alleviate muscular symptoms has also been attempted under these conditions, but with at least dubious, if not contradictory, results. One only has to read the debate on the subject in the case of ME/CFS patients to understand the difficulty of giving a meaningful answer to the question: does planned physical activity help or harm the duration and intensity of the symptom of chronic fatigue?3 As we hypothesise in the last part of our article,4 we think it is crucial to identify the molecular mechanism underlying the atrophic effect (if any) of the described disease states, which could originate from a local (muscular) inflammatory storm induced by Spike binding to the ACE-2 receptor in muscle.5 When studies on muscle material from patients are available in sufficient numbers, we will be able to try to answer the question posed above. List of acronyms COVID - coronavirus disease ME/CFS - Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome SARS-CoV-2 - Severe Acute Respiratory Syndrome by Corona virus 2 Contributions of Authors The authors read and approved the final edited manuscript. Acknowledgments None. Funding This research received no external funding. Physical activity and long COVID fatigue Eur J Transl Myol 33 (3) 11804, 2023 doi: 10.4081/ejtm.2023.11804 - 2 - Conflict of Interest The authors declare they have no fconflicts of interest. Ethical Publication Statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Corresponding Author Giorgio Fanò-Illic, Campus of Free University of Alcatraz, Free University of Alcatraz, Santa Cristina di Gubbio, 06024 Gubbio, Italy. ORCID iD: 0000-0002-8753-5707 Email: fanoillic@gmail.com E-mails and ORCID iD of co-authors Francesco Coscia: francesco.coscia1@gmail.com ORCID iD: 0000-0003-1900-0302 Ester Sara Di Filippo: es.difilippo@unich.it ORCID iD 0000-0001-9531-7788 Paola Virginia Gigliotti: Italy; pao.gigliotti@gmail.com ORCID iD: 0000-0002-8908-4153 References 1. Daungsupawong F, Wiwanitkit V. Comments on: Effect of physical activity on long COVID fatigue Eur J Transl Myol. 2023 Sep 15. doi: 1.4081/ejtm.2023.11722. Online ahead of print. 2. Marks DF. Converging Evidence of Similar Symptomatology of ME/CFS and PASC Indicating Multisystemic Dyshomeostasis. Biomedicines. 2023 Jan 11;11(1):180. doi: 10.3390/biomedicines11010180. PMID: 36672687; PMCID: PMC9855891. 3. Joseph P, Singh I, Oliveira R, Capone CA, Mullen MP, Cook DB, Stovall MC, Squires J, Madsen K, Waxman AB, Systrom DM. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2: More in Common Than Not? Chest. 2023 Sep;164(3):717- 726. doi: 10.1016/j.chest.2023.03.049. Epub 2023 Apr 11. PMID: 37054777; PMCID: PMC10088277.. 4. Coscia F, Di Filippo ES, Gigliotti PV, Fano Illic G. Effect of physical activity on long COVID fatigue: an unsolved enigma. Eur J Transl Myol. 2023 Sep 4. doi: 10.4081/ejtm.2023.11639. Online ahead of print. PMID: 37667865. 5. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol (1985). 2020 Oct 1;129(4):864-867. doi: 10.1152/japplphysiol.00321.2020. Epub 2020 Jul 16. PMID: 32673162; PMCID: PMC7832004. Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submission: September 14, 2023 Accepted for publication: September 14, 2023 mailto:fanoillic@gmail.com mailto:francesco.coscia1@gmail.com mailto:es.difilippo@unich.it mailto:pao.gigliotti@gmail.com