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Zinc finger BED\u2010type containing 6 (ZBED6), a transcriptional repressor, enhances muscle growth and protects against sepsis\u2010induced atrophy, but its role in ageing\u2010 and dexamethasone (Dex)\u2010induced muscle atrophy remains unknown. This study investigated the protective role of ZBED6 knockout (KO) against muscle atrophy through the Dkk3\u2010Fbxo32 pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The muscle mass, ratio and myofibrillar morphology of 5\u2010day\u2010old (wild\u2010type (WT): KO, <jats:italic>n<\/jats:italic>\u2009=\u20095:3), 5\u2010month\u2010old (<jats:italic>n<\/jats:italic>\u2009=\u20098:9) and 8\u2010month\u2010old (<jats:italic>n<\/jats:italic>\u2009=\u20093:3) ZBED6\u2010KO pigs and 18\u2010month\u2010old mice (<jats:italic>n<\/jats:italic>\u2009=\u20093:3) were analysed. A model of Dex\u2010induced muscle atrophy was established using 3\u2010month\u2010old mice (<jats:italic>n<\/jats:italic>\u2009=\u20096:6) via intraperitoneal injections (15\u2009mg\/kg\/day for 10\u2009days). C2C12 myotubes were treated with 100\u2009\u03bcM Dex for 24\u2009h. Muscle morphology was analysed through H&amp;E and immunofluorescence staining. Gene expression was assessed through RNA\u2010seq, qRT\u2010PCR and western blotting. The downstream targets were identified through ChIP\u2010seq using anti\u2010ZBED6 antibodies and RNA\u2010seq analysis of the gastrocnemius muscle from ZBED6\u2010KO and WT pigs. Dkk3 was overexpressed by injecting AAV9\u2010myo2A\u2010Dkk3 (2\u2009\u00d7\u200910<jats:sup>11<\/jats:sup>) into the tibialis anterior muscle of 3\u2010month\u2010old ZBED6\u2010KO mice (<jats:italic>n<\/jats:italic>\u2009=\u20094), which were harvested 1\u2009month postinjection. ZBED6\u2010KO C2C12 cells were generated via CRISPR\/Cas9 and treated with Dex to assess the effects on myotube diameter and gene expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The muscle mass and muscle\u2010to\u2010carcass ratio in ZBED6\u2010KO pigs increased by 27% and 12%, respectively (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), while the Dkk3\u2010Fbxo32 pathway was suppressed by 50% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). ChIP\u2010seq\/RNA\u2010seq identified Dkk3 as the most significant ZBED6 target (log2FC\u2009=\u2009\u22123.38, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). The myofibrillar cross\u2010sectional areas (CSAs) increased twofold in aged ZBED6\u2010KO mice, while fibrosis and the Dkk3\u2010Fbxo32 pathway were suppressed by 76% and 50%, respectively (all <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Dkk3 overexpression reduced the tibialis anterior muscle weight and CSA in ZBED6\u2010KO mice by 31% and 61%, respectively (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Dex reduced the CSA in WT mice (45%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), but ZBED6\u2010KO mice resisted atrophy (CSA similar to untreated WT). ZBED6\u2010KO increased myotube diameter by twofold (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and inhibited the activation of the Dkk3\u2010Fbxo32 pathway (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Conversely, <jats:italic>Zbed6<\/jats:italic> overexpression reduced the CSA and myotube diameter by 32% and 64%, respectively (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and rescued by Dkk3 silencing (50% recovery, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>ZBED6 depletion mitigates ageing\u2010 and Dex\u2010induced muscle atrophy via the Dkk3\u2010Fbxo32 axis, highlighting its therapeutic potential.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13829","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T11:04:45Z","timestamp":1749726285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["ZBED6 Knockout Prevents Ageing\u2010 and Dexamethasone\u2010Induced Muscle Atrophy via Dkk3 in Pig and Mice"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2282-5268","authenticated-orcid":false,"given":"Chengjie","family":"Wei","sequence":"first","affiliation":[{"name":"Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"},{"name":"National Germplasm Center of Domestic Animal Resources, Ministry of Science and Technology of the People's Republic of China, Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"},{"name":"National Germplasm Center of Domestic Animal Resources, Ministry of Science and Technology of the People's Republic of China, Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitian","family":"Ma","sequence":"additional","affiliation":[{"name":"Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"},{"name":"National Germplasm Center of Domestic Animal Resources, Ministry of Science and Technology of the People's Republic of China, Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"},{"name":"National Germplasm Center of Domestic Animal Resources, Ministry of Science and Technology of the People's Republic of China, Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengke","family":"Pan","sequence":"additional","affiliation":[{"name":"Institute of Organ Transplantation Sichuan Academy of Medical Sciences &amp; Sichuan Provincial People's Hospital  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehui","family":"Ma","sequence":"additional","affiliation":[{"name":"Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Science Chinese Academy of Agricultural Sciences (CAAS)  Beijing China"},{"name":"National Germplasm Center of Domestic Animal Resources, Ministry of Science and Technology of the People's Republic of China, 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