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This study aimed to characterize phenotypic and transcriptomic skeletal muscle changes in middle\u2010aged individuals during disuse and rehabilitation. Eleven healthy middle\u2010aged adults (6 males, 5 females; age; 57\u2009\u00b1\u20095\u2009years) underwent 7\u2009days of unilateral lower limb suspension (ULLS). Following disuse, participants participated in a rehabilitation program consisting of either a lower\u2010body resistance exercise (RE) or walking control (WC) three times weekly for 2\u2009weeks. Bilateral skeletal muscle biopsies were collected at Day 0 and Day 7 of disuse and 2\u2009h post\u2010exercise on Days 7, 9, 11, and 21. Strength testing was conducted, and RNA sequencing was performed on muscle samples. Seven days of disuse reduced knee extension strength (14%; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and isometric force (13%; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Over\u2010representation analysis revealed a downregulation of mRNAs related to cellular respiration and NADH dehydrogenase complex assembly. Resistance exercise induced robust, but different, transcriptional changes in both disuse\u2010 and control\u2010legs. Walking had minimal effect on the muscle transcriptome. We conclude that 7\u2009days of disuse reduced leg strength, decreased mitochondrial gene expression, and increased inflammation and apoptosis\u2010related genes. We also conclude that resistance exercise enhanced recovery from disuse by improving strength, associated with significant transcriptomic changes.<\/jats:p>","DOI":"10.14814\/phy2.70497","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T08:17:01Z","timestamp":1754554621000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Transcriptomic time course of skeletal muscle disuse and rehabilitation in middle\u2010aged adults"],"prefix":"10.14814","volume":"13","author":[{"given":"Zachary D.","family":"Von Ruff","sequence":"first","affiliation":[{"name":"Department of Nutrition &amp; Metabolism University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean P.","family":"Kilroe","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity &amp; Aging Studies, University of Texas Health Science Center at San Antonio  San Antonio Texas USA"},{"name":"Department of Cellular &amp; Integrative Physiology University of Texas Health Science Center at San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik D.","family":"Marchant","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity &amp; Aging Studies, University of Texas Health Science Center at San Antonio  San Antonio Texas USA"},{"name":"Department of Cellular &amp; Integrative Physiology University of Texas Health Science Center at San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J.","family":"Arentson\u2010Lantz","sequence":"additional","affiliation":[{"name":"Department of Nutrition &amp; Metabolism University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Widen","sequence":"additional","affiliation":[{"name":"Next Generation Sequencing Core Facility University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Thompson","sequence":"additional","affiliation":[{"name":"Next Generation Sequencing Core Facility University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Villasante\u2010Tezanos","sequence":"additional","affiliation":[{"name":"Department of Biostatistics &amp; 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