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This study aimed to determine whether 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> deficiency could cause cellular senescence and a senescence\u2010associated secretory phenotype (SASP) in skeletal muscle cells to induce sarcopenia, whether GATA4 could be upregulated by 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> deficiency to promote SASP, and whether Bmi\u20101 reduces the expression of GATA4 and GATA4\u2010dependent SASP induced by 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> deficiency in skeletal muscle cells. Bioinformatics analyses with RNA sequencing data in skeletal muscle from physiologically aged and young mice were conducted. Skeletal muscles from 2\u2010month\u2010old young and 2\u2010year\u2010old physiologically aged wild\u2010type (WT) mice and 8\u2010week\u2010old WT, <jats:italic>Bmi\u20101<\/jats:italic> mesenchymal transgene (<jats:italic>Bmi\u20101<\/jats:italic><jats:sup><jats:italic>Tg<\/jats:italic><\/jats:sup>), <jats:italic>Cyp27b1<\/jats:italic> homozygous (<jats:italic>Cyp27b1<\/jats:italic><jats:sup><jats:italic>\u2212<\/jats:italic>\/<jats:italic>\u2212<\/jats:italic><\/jats:sup>), and <jats:italic>Bmi\u20101<\/jats:italic><jats:sup><jats:italic>Tg<\/jats:italic><\/jats:sup><jats:italic>Cyp27b1<\/jats:italic><jats:sup><jats:italic>\u2212<\/jats:italic>\/<jats:italic>\u2212<\/jats:italic><\/jats:sup> mice were observed for grip strength, cell senescence, DNA damage, and NF\u2010\u03baB\u2010mediated SASP signaling of skeletal muscle. We found that muscle\u2010derived Bmi\u20101 and vitamin D receptor (VDR) decreased with physiological aging, and DNA damage and GATA4\u2010dependent SASP activation led to sarcopenia. Furthermore, 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> deficiency promoted DNA damage\u2010induced GATA4 accumulation in muscles. GATA4 upregulated <jats:italic>Rela<\/jats:italic> at the region from \u22121448 to \u22121412\u2009bp at the transcriptional level to cause NF\u2010\u03baB\u2010dependent SASP for aggravating cell senescence and muscular dysfunction and sarcopenia. <jats:italic>Bmi\u20101<\/jats:italic> overexpression promoted the ubiquitination and degradation of GATA4 by binding RING1B, which prevented cell senescence, SASP, and dysfunctional muscle, and improved sarcopenia induced by 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> deficiency. Thus, Bmi\u20101 overexpression improves sarcopenia induced by 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> deficiency, downregulates GATA4<jats:italic>\u2010<\/jats:italic>dependent <jats:italic>Rela<\/jats:italic> transcription, and sequentially inhibits GATA4\u2010dependent SASP in muscle cells. Therefore, Bmi\u20101 overexpression could be used for translational gene therapy for the ubiquitination of GATA4 and prevention of sarcopenia. \u00a9 2023 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4770","type":"journal-article","created":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T11:59:56Z","timestamp":1673351996000},"page":"427-442","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Bmi\u20101 Overexpression Improves Sarcopenia Induced by 1,25(<scp>OH<\/scp>)<scp><sub>2<\/sub>D<sub>3<\/sub><\/scp> Deficiency and Downregulates <scp>GATA4<\/scp>\u2010Dependent <i>Rela<\/i> Transcription"],"prefix":"10.1093","volume":"38","author":[{"given":"Qiuyi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Human Anatomy, Research Centre for Bone and Stem Cells; Key Laboratory for Aging &amp; Disease; The State Key Laboratory of Reproductive Medicine Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Research Centre for Bone and Stem Cells; Key Laboratory for Aging &amp; Disease; The State Key Laboratory of Reproductive Medicine Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Research Centre for Bone and Stem Cells; Key Laboratory for Aging &amp; Disease; The State Key Laboratory of Reproductive Medicine Nanjing Medical University  Nanjing Jiangsu China"},{"name":"Medical School of Nanjing University, Jiangsu Laboratory of Molecular Medicine Nanjing University  Nanjing Jiangsu 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