{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:54:31Z","timestamp":1787313271706,"version":"build-2736575974"},"reference-count":51,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01\u2010AR078903"],"award-info":[{"award-number":["R01\u2010AR078903"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Volumetric muscle loss (VML) is the traumatic loss of skeletal muscle, resulting in chronic functional deficits and pathological comorbidities, including altered whole\u2010body metabolic rate and respiratory exchange ratio (RER), despite no change in physical activity in animal models. In other injury models, treatment with \u03b2<jats:sub>2<\/jats:sub> receptor agonists (e.g. formoterol) improves metabolic and skeletal muscle function. We aimed first to examine if restricting physical activity following injury affects metabolic and skeletal muscle function, and second, to enhance the metabolic and contractile function of the muscle remaining following VML injury through treatment with formoterol. Adult male C57Bl\/6J mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a032) underwent VML injury to the posterior hindlimb compartment and were randomly assigned to unrestricted or restricted activity and formoterol treatment or no treatment; age\u2010matched injury na\u00efve mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a04) were controls for biochemical analyses. Longitudinal 24\u00a0h evaluations of physical activity and whole\u2010body metabolism were conducted following VML. <jats:italic>In vivo<\/jats:italic> muscle function was assessed terminally, and muscles were biochemically evaluated for protein expression, mitochondrial enzyme activity and untargeted metabolomics. Restricting activity chronically after VML had the greatest effect on physical activity and RER, reflected in reduced lipid oxidation, although changes were attenuated by formoterol treatment. Formoterol enhanced injured muscle mass, while mitigating functional deficits. These novel findings indicate physical activity restriction may recapitulate following VML clinically, and adjunctive oxidative treatment may create a metabolically beneficial intramuscular environment while enhancing the injured muscle's mass and force\u2010producing capacity. Further investigation is needed to evaluate adjunctive oxidative treatment with rehabilitation, which may augment the muscle's regenerative and functional capacity following VML.\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\/tjp15403-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/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>The natural ability of skeletal muscle to regenerate and recover function is lost following complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), and physical inactivity following VML may incur additional deleterious consequences for muscle and metabolic health.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Modelling VML injury\u2010induced physical activity restriction altered whole\u2010body metabolism, primarily by decreasing lipid oxidation, while preserving local skeletal muscle metabolic activity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The \u03b2<jats:sub>2<\/jats:sub> adrenergic receptor agonist formoterol has shown promise in other severe injury models to improve regeneration, recover function and enhance metabolism. Treatment with formoterol enhanced mass of the injured muscle and whole\u2010body metabolism while mitigating functional deficits resulting from injury.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Understanding of chronic effects of the clinically available and FDA\u2010approved pharmaceutical formoterol could be a translational option to support muscle function after VML injury.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp283959","type":"journal-article","created":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T05:13:17Z","timestamp":1671513197000},"page":"743-761","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Restricted physical activity after volumetric muscle loss alters whole\u2010body and local muscle 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