{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T01:21:18Z","timestamp":1790990478233,"version":"4.1.0"},"reference-count":107,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T00:00:00Z","timestamp":1721347200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Skeletal muscle wasting is the hallmark pathophysiological adaptation to unloading or disuse that demonstrates the dependency on frequent mechanical stimulation (e.g. muscle activation and subsequent loading) for homeostasis of normally load\u2010bearing muscles. In the absence of mitigation strategies, no mammalian organism is resistant to muscle atrophy driven by unloading. Given the profound impact of unloading\u2010induced muscle wasting on physical capacity, metabolic health and immune function; mitigation strategies during unloading and\/or augmentation approaches during recovery have broad healthcare implications in settings of bed\u2010bound hospitalization, cast immobilization and spaceflight. This topical review aims to: (1) provide a succinct, state\u2010of\u2010the\u2010field summary of seminal and recent findings regarding the mechanisms of unloading\u2010induced skeletal muscle wasting; (2) discuss unsuccessful <jats:italic>vs<\/jats:italic>. promising mitigation and recovery augmentation strategies; and (3) identify knowledge gaps ripe for future research. We focus on the rapid muscle atrophy driven by relatively short\u2010term mechanical unloading\/disuse, which is in many ways mechanistically distinct from both hypermetabolic muscle wasting and denervation\u2010induced muscle atrophy. By restricting this discussion to mechanical unloading during which all components of the nervous system remain intact (e.g. without denervation models), mechanical loading requiring motor and sensory neural circuits in muscle remain viable targets for both mitigation and recovery augmentation. We emphasize findings in humans with comparative discussions of studies in rodents which enable elaboration of key mechanisms. We also discuss what is currently known about the effects of age and sex as biological factors, and both are highlighted as knowledge gaps and novel future directions due to limited research.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16198-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1113\/jp284301","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T15:28:53Z","timestamp":1721402933000},"page":"3641-3652","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Mitigating skeletal muscle wasting in unloading and augmenting subsequent recovery"],"prefix":"10.1113","volume":"603","author":[{"given":"J. Max","family":"Michel","sequence":"first","affiliation":[{"name":"School of Kinesiology Auburn University  Auburn Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Hettinger","sequence":"additional","affiliation":[{"name":"Discovery Center for Musculoskeletal Recovery, Spaulding Rehabilitation Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrisia","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"Discovery Center for Musculoskeletal Recovery, Spaulding Rehabilitation Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8327-9016","authenticated-orcid":false,"given":"Brendan","family":"Egan","sequence":"additional","affiliation":[{"name":"School of Health &amp; Human Performance Dublin City University  Dublin Ireland"},{"name":"Healthspan, 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