{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T17:32:04Z","timestamp":1789061524944,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Voluntary exercise improves clinical outcomes in healthy subjects, but increased muscle ammoniagenesis may limit beneficial responses during hyperammonaemia in chronic diseases. Responses to 4\u2010weeks voluntary wheel running (VWR) were compared with usual activity (UA) to determine if hyperammonaemia alters VWR responses and if VWR alters muscle responses to hyperammonaemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eight\u2010 to 10\u2010week\u2010old male C57BL\/6J mice were treated with 6\u2009weeks of subcutaneous infusion of 2.5\u2009mmol\u2009kg<jats:sup>\u22121<\/jats:sup>\u2009day<jats:sup>\u22121<\/jats:sup> ammonium acetate (AmAc) or vehicle (PBS) via an osmotic pump. Two weeks after the start of infusion, mice were assigned to the intervention (VWR or UA). Wheel runs were measured, and weekly average rotations, distance, and circadian patterns were analysed. Indirect calorimetry was performed pre\u2010 and post\u2010intervention. Mice were euthanized 4\u2009weeks after the start of VWR\/UA, and organs (including muscles) were harvested, weighed, and muscle histomorphometry performed for fibre diameter\/type. Protein synthesis by ex\u00a0vivo puromycin incorporation, autophagy markers, expression of signalling proteins (mTORC1 pathway, eukaryotic initiation factor\u20102\u2010\u03b1 phosphorylation), and ammonia disposal enzymes were quantified by immunoblots. Mitochondrial oxidative function was measured by high\u2010sensitivity respirofluorometry using substrate, uncoupler, inhibitor, and titration protocols. Fluorometric assays were done for ammonia measurements.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Gastrocnemius muscle mass (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), muscle fibre area (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), and grip strength were lower in AmAc\u2010UA than in PBS\u2010UA mice and higher with VWR than UA in AmAc mice (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Expression of electron transport chain proteins and some components of mitochondrial oxidative function were less (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05 or less) in AmAc\u2010UA than PBS\u2010UA, and these perturbations were reversed in the AmAc\u2010VWR mice (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05 or less). Global muscle protein synthesis (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and components of the mTORC1 pathway expression (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) were higher, while myostatin expression was lower with VWR than UA in AmAc mice (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Expression of autophagy markers P62 and LC3\u2010II was not different with VWR or UA in AmAc mice, while Beclin1 was higher in VWR compared with UA, regardless of treatment group (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Expression of muscle ammonia disposal pathway enzymes, including glutamate dehydrogenase and pyrroline\u20105\u2010carboxylate synthase, was higher (<jats:italic>p<\/jats:italic>\u2009\u2264\u20090.05) in AmAc\u2010UA versus PBS\u2010UA and increased in only PBS\u2010VWR mice (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>VWR reverses hyperammonaemia\u2010induced sarcopenia, protein synthesis\/autophagy signalling perturbations, and mitochondrial oxidative dysfunction. Muscle mass, grip strength, signalling, and mitochondrial responses to VWR were not affected by hyperammonaemia. Increased expression of enzymes involved in the ammonia disposal pathway in skeletal muscle may be an adaptive response to hyperammonaemia. These data provide the rationale for exercise programmes in chronic diseases, including cirrhosis, even with hyperammonaemia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.70031","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T05:21:30Z","timestamp":1754371290000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Voluntary Activity Wheel Running Improves Hyperammonaemia\u2010Induced Skeletal Muscle Molecular and Metabolic Perturbations in Mice"],"prefix":"10.1002","volume":"16","author":[{"given":"Annette","family":"Bellar","sequence":"first","affiliation":[{"name":"Department of Inflammation and Immunity Lerner Research Institute Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avinash","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Human Nutrition All India Institute of 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