{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:46:57Z","timestamp":1786978017019,"version":"build-2736575974"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T00:00:00Z","timestamp":1644364800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2019A1515110402"],"award-info":[{"award-number":["2019A1515110402"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32100915"],"award-info":[{"award-number":["32100915"]}],"id":[{"id":"10.13039\/501100001809","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":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Skeletal muscle atrophy is a common clinical manifestation of various neurotrauma and neurological diseases. In addition to the treatment of primary neuropathies, it is a clinical condition that should be investigated. FoxO3 activation is an indispensable mechanism in denervation\u2010induced muscle atrophy; however, upstream factors that control FoxO3 expression and activity have not been fully elucidated. N\n                      <jats:sup>6<\/jats:sup>\n                      \u2010methyladenosine (m\n                      <jats:sup>6<\/jats:sup>\n                      A) methylation is a novel mode of epitranscriptional gene regulation that affects several cellular processes. However, the biological significance of m\n                      <jats:sup>6<\/jats:sup>\n                      A modification in FoxO3\u2010dependent atrophy is unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed gain\u2010of\u2010function and loss\u2010of\u2010function experiments and used denervation\u2010induced muscle atrophy mouse model to evaluate the effects of m\n                      <jats:sup>6<\/jats:sup>\n                      A modification on muscle mass control and FoxO3 activation. m\n                      <jats:sup>6<\/jats:sup>\n                      A\u2010sequencing and mass spectrometry analyses were used to establish whether histone deacetylase 4 (HDAC4) is a mediator of m\n                      <jats:sup>6<\/jats:sup>\n                      A demethylase ALKBH5 regulation of FoxO3. A series of cellular and molecular biological experiments (western blot, immunoprecipitation, half\u2010life assay, m\n                      <jats:sup>6<\/jats:sup>\n                      A\u2010MeRIP\u2010qPCR, and luciferase reporter assays among others) were performed to investigate regulatory relationships among ALKBH5, HDAC4, and FoxO3.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In skeletal muscles, denervation was associated with a 20.7\u201331.9% decrease in m\n                      <jats:sup>6<\/jats:sup>\n                      A levels (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01) and a 35.6\u2013115.2% increase in demethylase ALKBH5 protein levels (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05). Overexpressed ALKBH5 reduced m\n                      <jats:sup>6<\/jats:sup>\n                      A levels, activated FoxO3 signalling, and induced excess loss in muscle wet weight (\u221210.3% for innervation and \u221211.4% for denervation,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) as well as a decrease in myofibre cross\u2010sectional areas (\u221235.8% for innervation and \u221233.3% for denervation,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) during innervation and denervation. Specific deletion of\n                      <jats:italic>Alkbh5<\/jats:italic>\n                      in the skeletal muscles prevented FoxO3 activation and protected mice from denervation\u2010induced muscle atrophy, as evidenced by increased muscle mass (+16.0%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05), size (+50.0%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05) and MyHC expression (+32.6%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05). Mechanistically, HDAC4 was established to be a crucial central mediator for ALKBH5 in enhancing FoxO3 signalling in denervated muscles. ALKBH5 demethylates and stabilizes\n                      <jats:italic>Hdac4<\/jats:italic>\n                      mRNA. HDAC4 interacts with and deacetylates FoxO3, resulting in a significant increase in FoxO3 expression (+61.3\u201382.5%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.01) and activity (+51.6\u2013122.0%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings elucidate on the roles and mechanisms of ALKBH5\u2010mediated m\n                      <jats:sup>6<\/jats:sup>\n                      A demethylation in the control of muscle mass during denervation and activation of FoxO3 signalling by targeting HDAC4. These results suggest that ALKBH5 is a potential therapeutic target for neurogenic muscle atrophy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.12929","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:51:24Z","timestamp":1644454284000},"page":"1210-1223","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["m\n                    <sup>6<\/sup>\n                    A demethylase ALKBH5 drives denervation\u2010induced muscle atrophy by targeting HDAC4 to activate FoxO3 signalling"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3672-2489","authenticated-orcid":false,"given":"Yuantong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Spine Surgery Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University  Shenzhen China"},{"name":"Department of Orthopedics Qilu 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