{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T12:02:17Z","timestamp":1779796937394,"version":"3.53.1"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sibylla-Hesse Foundation"},{"name":"The Open Medicine Foundation Canada"},{"name":"The National MEFM Action Network"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Myalgic Encephalomyelitis (ME) is a chronic, multisystem disease characterized by systemic metabolic dysfunction and post-exertional malaise (PEM). In this study, we investigated the dysregulation of irisin, an exercise-induced myokine, and its potential antagonism by thrombospondin-1 (TSP-1). In a cross-sectional study (92 ME patients vs. 44 sedentary healthy controls), plasma irisin and TSP-1 levels were measured at baseline and after a 90 min mechanical stress challenge applied to induce PEM. ME patients exhibited significantly lower baseline irisin (p &lt; 0.05) and a blunted exertional response (p &lt; 0.05). Paradoxically, baseline irisin was an independent predictor of fatigue severity (\u03b2 = 0.728, p = 0.018), with moderate-to-severe patients showing elevated levels of both irisin and TSP-1 (p &lt; 0.05), suggesting a compensatory but ineffective response. Functional cellular dielectric spectroscopy indicated that TSP-1 inhibits irisin signaling in a concentration-dependent manner. Irisin signaling was markedly reduced by both \u03b1v\u03b25 blockade and HSP90\u03b1 inhibition in this experimental system, consistent with a diminished ability to counteract TSP-1. Collectively, these findings support a model in which dysregulation of the irisin\u2013TSP-1 axis contributes to metabolic dysfunction in ME. Elevated circulating TSP-1 levels are associated with symptom severity and are linked to impaired irisin signaling in an HSP90\u03b1- and \u03b1v\u03b25-dependent context. This interaction is consistent with defective metabolic adaptation and highlights a potential therapeutic target that warrants further validation to restore energy homeostasis.<\/jats:p>","DOI":"10.3390\/ijms27114770","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:16:08Z","timestamp":1779783368000},"page":"4770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Irisin Signaling Resistance in Myalgic Encephalomyelitis: A Proposed Mechanistic Framework for Post-Exertional Malaise Involving the TSP-1\u2013HSP90\u03b1\u2013\u03b1v\u03b25 Axis"],"prefix":"10.3390","volume":"27","author":[{"given":"Bernard","family":"Souma","sequence":"first","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"Patient-Partner, ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3577-3551","authenticated-orcid":false,"given":"Wesam","family":"Elremaly","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"Patient-Partner, ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Yvonne","family":"Akoume","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"Patient-Partner, ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Cellular and Molecular Biology and Genetics, Institut Sup\u00e9rieur de Biologie M\u00e9dicale (ISBM), Universit\u00e9 des Sciences de la Sant\u00e9 (USS) de Libreville, Libreville P.O. Box 18231, Gabon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3301-069X","authenticated-orcid":false,"given":"Mohamed","family":"Elbakry","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"Patient-Partner, ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Biochemistry Section, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Godbout","sequence":"additional","affiliation":[{"name":"Patient-Partner, ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1144-6174","authenticated-orcid":false,"given":"Alain","family":"Moreau","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"Patient-Partner, ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Stomatology, Faculty of Dentistry, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19620","DOI":"10.1038\/s41598-020-76438-y","article-title":"Profile of circulating microRNAs in myalgic encephalomyelitis and their relation to symptom severity, and disease pathophysiology","volume":"10","author":"Nepotchatykh","year":"2020","journal-title":"Sci. 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