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Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut\u2010released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long\u2010term effects of UnAG in age\u2010associated muscle atrophy and contractile dysfunction in mice. Four\u2010month\u2010old and 18\u2010month\u2010old mice were subjected to either UnAG or control treatment for 10\u2009months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%\u201330% with age, which was partially protected against by UnAG. Specific force, force per cross\u2010sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA\u2010seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.<\/jats:p>","DOI":"10.1111\/acel.14323","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T04:01:07Z","timestamp":1725336067000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Unacylated Ghrelin Protects Against Age\u2010Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle"],"prefix":"10.1111","volume":"23","author":[{"given":"Hyunyoung","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Wake Forest University School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rojina","family":"Ranjit","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma Medical Research Foundation  Oklahoma City Oklahoma USA"},{"name":"Department of Biochemistry University of Oklahoma Health Sciences Center  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis R.","family":"Claflin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Michigan  Ann Arbor Michigan USA"},{"name":"Department of Molecular and Integrative Physiology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Georgescu","sequence":"additional","affiliation":[{"name":"Genes and Human Disease Research Program Oklahoma Medical Research Foundation  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Wren","sequence":"additional","affiliation":[{"name":"Genes and Human Disease Research Program Oklahoma Medical Research Foundation  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan V.","family":"Brooks","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Michigan  Ann Arbor Michigan USA"},{"name":"Department of Molecular and Integrative Physiology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin F.","family":"Miller","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program Oklahoma Medical Research Foundation  Oklahoma City Oklahoma USA"},{"name":"Oklahoma City VA Medical Center  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2743-7099","authenticated-orcid":false,"given":"Bumsoo","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Wake Forest University School of Medicine  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