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Retinol binding protein 4 (RBP4) is an adipokine that has been demonstrated to be correlated with the presence and severity of sarcopenia in the elderly. However, the exact role and the underlying mechanism of RBP4 in muscle atrophy remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Denervation\u2010induced muscle atrophy model was constructed in wild\u2010type and RBP4 knockout mice. To modify the expression of RBP4, mice were received intramuscular injection of retinol\u2010free RBP4 (apo\u2010RBP4), retinol\u2010bound RBP4 (holo\u2010RBP4) or oral gavage of RBP4 inhibitor A1120. Holo\u2010RBP4\u2010stimulated C2C12 myotubes were treated with siRNAs or specific inhibitors targeting signalling receptor and transporter of retinol 6 (STRA6)\/Janus kinase 2 (JAK2)\/Signal transducer and activator of transcription 3 (STAT3) pathway. Fat accumulation, myofibre cross\u2010sectional area, myotube diameter and the expression of muscle atrophy markers and myogenesis markers were analysed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The expression levels of RBP4 in skeletal muscles were significantly up\u2010regulated more than 2\u2010fold from 7\u00a0days and sustained for 28\u00a0days after denervation. Immunofluorescence analysis indicated that increased RBP4 was localized in the infiltrated fatty region in denervated skeletal muscles. Knockout of RBP4 alleviated denervation\u2010induced fatty infiltration and muscle atrophy together with decreased expression of atrophy marker Atrogin\u20101 and MuRF1 as well as increased expression of myogenesis regulators MyoD and MyoG. By contrast, injection of retinol\u2010bound holo\u2010RBP4 aggregated denervation\u2010induced ectopic fat accumulation and muscle atrophy. Consistently, holo\u2010RBP4 stimulation also had a dose\u2010dependent effect on the reduction of C2C12 myotube diameter and myofibre cross\u2010sectional area, as well as on the increase of Atrogin\u20101and MuRF1 expression and decrease of MyoD and MyoG expression. Mechanistically, holo\u2010RBP4 treatment increased the expression of its membrane receptor STRA6 (&gt;3\u2010fold) and promoted the phosphorylation of downstream JAK2 and STAT3. Inhibition of STRA6\/JAK2\/STAT3 pathway either by specific siRNAs or inhibitors could decrease the expression of Atrogin\u20101 and MuRF1 (&gt;50%) and decrease the expression of MyoD and MyoG (&gt;3\u2010fold) in holo\u2010RBP4\u2010treated C2C12 myotube. RBP4 specific pharmacological antagonist A1120 significantly inhibited the activation of STRA6\/JAK2\/STAT3 pathway, ameliorated ectopic fat infiltration and protected against denervation\u2010induced muscle atrophy (30% increased myofibre cross\u2010sectional area) in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In conclusion, our data reveal that RBP4 promotes fat infiltration and muscle atrophy through a STRA6\u2010dependent and JAK2\/STAT3 pathway\u2010mediated mechanism in denervated skeletal muscle. Our results suggest that lowering RBP4 levels might serve as a promising therapeutic approach for prevention and treatment of muscle atrophy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13518","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T12:56:06Z","timestamp":1718974566000},"page":"1601-1615","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["RBP4 promotes denervation\u2010induced muscle atrophy through STRA6\u2010dependent pathway"],"prefix":"10.1002","volume":"15","author":[{"given":"Kang\u2010Zhen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Geriatrics, Zhongda Hospital, School of Medicine Southeast University  No. 87 Dingjiaqiao Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Zhongda Hospital, School of Medicine Southeast University  No. 87 Dingjiaqiao Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010Shui","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Province Center for Disease Control and Prevention  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng\u2010Kai","family":"Shen","sequence":"additional","affiliation":[{"name":"Jiangsu Province Center for Disease Control and Prevention  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Shuang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Geriatrics Sir Run Run Hospital, Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Geriatrics Sir Run Run Hospital, Nanjing Medical University  Nanjing 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