{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:39:27Z","timestamp":1790617167163,"version":"4.1.0"},"reference-count":111,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":34,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS) is a debilitating illness characterized by post\u2010exertional malaise (PEM), a worsening of symptoms following exertion. The biological mechanisms underlying PEM remain unclear. Extracellular vesicles (EVs) play a key role in cell\u2013cell communication and may provide insight into ME\/CFS pathophysiology post\u2010exertion. Emerging evidence suggests similarities between ME\/CFS and Long COVID, including PEM and overlapping immune and metabolic dysfunctions, highlighting the need for deeper mechanistic understanding.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study explores the EV proteome response to exercise in 10 males with ME\/CFS and 12 well\u2010matched sedentary male controls. Participants underwent a maximal cardiopulmonary exercise test, and plasma samples were collected at baseline, 15\u00a0min, and 24\u00a0h postexercise. EVs were isolated from plasma using size\u2010exclusion chromatography and characterized with nanoparticle tracking analysis. EV protein abundance was quantified with untargeted proteomics (nanoLC\u2010MS\/MS). Comprehensive analyses included differential abundance, pathway enrichment, protein\u2013protein interaction networks, and correlations between EV protein dynamics and clinical or exercise physiology data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ME\/CFS patients exhibited many significantly altered EV proteomic responses compared with controls, including downregulation of TCA cycle\u2010related proteins and upregulation of complement system proteins at 15\u00a0min postexercise. Changes in proteins involved in protein folding and the endoplasmic reticulum (ER) stress response during recovery were highly correlated with PEM severity, highlighting their potential as therapeutic targets. EV protein changes postexercise were also associated with disease severity and unrefreshing sleep. Correlations between EV protein levels and the exercise parameters VO\u2082 peak and ventilatory anaerobic threshold were observed in controls but were absent in ME\/CFS patients, suggesting disrupted EV\u2010mediated physiological processes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>ME\/CFS patients exhibit a maladaptive EV proteomic response to exercise, characterized by metabolic impairments, immune overactivation, and ER stress response dysregulation. These findings provide insight into the molecular basis of PEM and suggest promising targets for improving recovery and energy metabolism in ME\/CFS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>EVs were isolated from plasma of ME\/CFS patients and healthy controls at baseline, and 15 min and 24\u00a0h postexercise.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Untargeted proteomics revealed dysregulation in energy metabolism, the complement system, and the endoplasmic reticulum stress response.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Changes in EV protein levels postexercise are associated with post\u2010exertional malaise.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These findings suggest promising therapeutic targets for post\u2010exertional malaise and ME\/CFS pathophysiology.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70346","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T11:05:08Z","timestamp":1749035108000},"source":"Crossref","is-referenced-by-count":14,"title":["Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis\/chronic fatigue syndrome"],"prefix":"10.1002","volume":"15","author":[{"given":"Katherine A.","family":"Glass","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Giloteaux","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Facility Institute of Biotechnology Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8141-3058","authenticated-orcid":false,"given":"Maureen R.","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"e_1_2_12_2_1","volume-title":"Beyond myalgic encephalomyelitis\/chronic fatigue syndrome: Redefining an illness","author":"IOM 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