{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T20:06:09Z","timestamp":1792526769805,"version":"4.5.0"},"reference-count":143,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Skeletal muscle is increasingly recognized as a dynamic secretory organ capable of translating contractile, metabolic, mechanical and inflammatory stimuli into systemic biological signals. Among these signals, myokines and myokine-associated exerkines mediate communication between skeletal muscle and distant organs, influencing glucose and lipid metabolism, immune regulation, bone remodeling, neuroplasticity, vascular function and tissue regeneration. Representative mediators considered include IL-6, IL-15, myostatin, follistatin, decorin, FNDC5\/irisin, FGF21, myonectin\/CTRP15, BDNF, cathepsin B, SPARC, apelin and extracellular-vesicle cargo. However, current evidence remains fragmented across individual molecules, exercise modalities, sampling windows, assay platforms and disease contexts. This narrative mechanistic review proposes the concept of the \u201cmyokine adaptome\u201d as an integrated, context-dependent signaling network through which skeletal muscle contributes to systemic homeostasis in health and disease. We synthesize evidence on cellular triggers of myokine release, including AMPK-PGC-1\u03b1 signaling, mTORC1-dependent mechanical sensing, calcium flux, redox signaling, inflammatory pathways and extracellular-vesicle-mediated communication. We further examine how exercise modality, aging, obesity, type 2 diabetes, sarcopenia, osteoporosis, cardiovascular disease, COPD, cancer\/cachexia and chronic inflammation reshape myokine production and target-organ responsiveness. The central argument is that myokine biology should be interpreted not as a catalog of isolated mediators, but as a dynamic adaptive code defined by signal amplitude, temporal pattern, molecular composition, delivery route and recipient-tissue sensitivity. Its novelty is operational rather than nominal: it requires source confidence, temporal kinetics, co-signal context, delivery route and functional decoding to be evaluated together. This framework may improve biomarker design, disease-specific exercise prescription and therapeutic strategies aimed at restoring adaptive muscle\u2013organ communication. The framework is further strengthened by testable predictions concerning adaptive pulsatility, modality-specific signatures, source attribution, recovery quality, disease-specific decoding and the superiority of multi-marker panels over single-molecule readouts.<\/jats:p>","DOI":"10.3390\/cells15141236","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T08:50:56Z","timestamp":1783587056000},"page":"1236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Myokine Adaptome in Health and Disease: Exercise-Induced Cellular Signaling, Muscle\u2013Organ Crosstalk, and Therapeutic Plasticity"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9406-8555","authenticated-orcid":false,"given":"Dan Cristian","family":"M\u0103nescu","sequence":"first","affiliation":[{"name":"Department of Physical Education and Sports, Bucharest University of Economic Sciences, 010374 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6845-4610","authenticated-orcid":false,"given":"Camelia Daniela","family":"Plastoi","sequence":"additional","affiliation":[{"name":"Sport and Health Department, Faculty of Medical and Behavioral Sciences, Constantin Br\u00e2ncusi University of T\u00e2rgu-Jiu, 210135 Targu-Jiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0143-9679","authenticated-orcid":false,"given":"Ancu\u021ba","family":"P\u00eervan","sequence":"additional","affiliation":[{"name":"Department of Physical Education and Sports, Faculty of Humanities, Valahia University of T\u00e2rgoviste, 130105 Targoviste, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodica","family":"D\u00eernu","sequence":"additional","affiliation":[{"name":"Sport and Health Department, Faculty of Medical and Behavioral Sciences, Constantin Br\u00e2ncusi University of T\u00e2rgu-Jiu, 210135 Targu-Jiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Ancu\u021ba","family":"Floroiu","sequence":"additional","affiliation":[{"name":"Doctoral School in Sport Science and Physical Education, Pite\u0219ti University Center, National University of Science and Technology Politehnica Bucharest, 110040 Pitesti, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Popescu","sequence":"additional","affiliation":[{"name":"Sport and Health Department, Faculty of Medical and Behavioral Sciences, Constantin Br\u00e2ncusi University of T\u00e2rgu-Jiu, 210135 Targu-Jiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nrendo.2012.49","article-title":"Muscles, exercise and obesity: Skeletal muscle as a secretory organ","volume":"8","author":"Pedersen","year":"2012","journal-title":"Nat. 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