{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T13:57:21Z","timestamp":1780581441056,"version":"3.54.1"},"reference-count":37,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014943","name":"Sarepta Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014943","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Sarcopenia, an age\u2010related loss of muscle mass, is a critical factor that affects the health of the older adults. The SOD1KO mouse is deficient of Cu\/Zn superoxide dismutase, used as an accelerated aging model. We previously showed that NT\u20103 improves muscle fibre size by activating the mTOR pathway, suggesting a potential for attenuating age\u2010related muscle loss. This study assessed the therapeutic efficacy of AAV1.NT\u20103 in this accelerated aging model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twelve 6\u00a0months old SOD1KO mice were injected intramuscularly with a 1\u00a0\u00d7\u00a010<jats:sup>11<\/jats:sup> vg dose of AAV1.tMCK.NT\u20103, and 13 age\u2010matched SOD1KO mice were used as controls. The treatment effect was evaluated using treadmill, rotarod and gait analyses as well as histological studies assessing changes in muscle fibre, and fibre type switch, in tibialis anterior, gastrocnemius, and triceps muscles, and myelin thickness by calculating G ratio in sciatic and tibial nerves. Molecular studies involved qPCR experiments to analyse the expression levels of mitochondrial and glycolysis markers and western blot experiments to assess the activity of mTORC1 pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Treatment resulted in a 36% (154.9 vs. 114.1; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and 76% increase (154.3 vs. 87.6; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) in meters ran, with treadmill test at 3 and 6\u00a0months post gene delivery. In addition, the treated cohort stayed on rotarod 30% (52.7\u00a0s vs. 40.4\u00a0s; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0095) and 54% (50.4\u00a0s vs. 32.7\u00a0s; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0007) longer, compared with untreated counterparts at 3 and 6\u00a0months post injection. Gait analysis, performed at endpoint, showed that stride width was normalized to wild type levels (29.3\u00a0mm) by an 11% decrease, compared with untreated cohort (28.6\u00a0mm vs. 32.1\u00a0mm; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0014). Compared with wild\u2010type, SOD1KO mice showed 9.4% and 11.4% fibre size decrease in tibialis anterior and gastrocnemius muscles, respectively, which were normalized to wild type levels with treatment. Fibre diameter increase was observed prominently in FTG fibre type. G ratio analysis revealed hypomyelination in the tibial (0.721) and sciatic (0.676) nerves of SOD1KO model, which was reversed in the NT\u20103 cohort (0.646 and 0.634, respectively). Fibre size increase correlated with the increase in the p\u2010S6 and p\u20104E\u2010BP1 levels, and in the glycolysis markers in tibialis anterior. Alterations observed in the mitochondrial markers were not rescued with treatment. Overall, response to NT\u20103 was subdued in gastrocnemius muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study shows that AAV1.NT\u20103 gene therapy protected SOD1KO mouse from accelerated aging effects functionally and histologically. We further confirmed that NT\u20103 has potential to activate the mTOR and glycolytic pathways in muscle.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13303","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T23:40:50Z","timestamp":1691538050000},"page":"2204-2215","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["AAV1.NT\u20103 gene therapy in the SOD1KO mouse model of accelerated sarcopenia"],"prefix":"10.1002","volume":"14","author":[{"given":"Lingying","family":"Tong","sequence":"first","affiliation":[{"name":"Center for Gene Therapy The Abigail Wexner Research Institute, Nationwide Children's Hospital  Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burcak","family":"Ozes","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy The Abigail Wexner Research Institute, Nationwide Children's Hospital  Columbus OH 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