{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:03:11Z","timestamp":1790128991493,"version":"4.0.1"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2022YFA0806102"],"award-info":[{"award-number":["2022YFA0806102"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82230027"],"award-info":[{"award-number":["82230027"]}],"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":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Glucocorticoids (GCs) are the most important and frequently used class of anti\u2010inflammatory drugs. However, the mechanisms underlying excessive glucocorticoid\u2010mediated induction of muscle atrophy remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We generated skeletal muscle\u2010specific\n                      <jats:italic>Klf9<\/jats:italic>\n                      transgenic mice (m\n                      <jats:italic>Klf9<\/jats:italic>\n                      TG) and skeletal muscle\u2010specific\n                      <jats:italic>Klf9<\/jats:italic>\n                      knockout mice (\n                      <jats:italic>Klf9<\/jats:italic>\n                      <jats:sup>mlc\u2212\/\u2212<\/jats:sup>\n                      ). The body weight, tissue weight, body composition, grip strength, running distance and muscle fibre cross section of m\n                      <jats:italic>Klf9<\/jats:italic>\n                      TG,\n                      <jats:italic>Klf9<\/jats:italic>\n                      <jats:sup>mlc\u2212\/\u2212<\/jats:sup>\n                      mice and their littermate controls were examined. Expression of genes related to muscle protein synthesis and degradation pathways were also tested in the m\n                      <jats:italic>Klf9<\/jats:italic>\n                      TG mice,\n                      <jats:italic>Klf9<\/jats:italic>\n                      <jats:sup>mlc\u2212\/\u2212<\/jats:sup>\n                      mice and their littermate controls. We performed Klf9 gain\u2010 or loss\u2010of\u2010function studies in differentiated C2C12 myotubes using lentiviruses encoding\n                      <jats:italic>Klf9<\/jats:italic>\n                      or the shRNA specific to\n                      <jats:italic>Klf9<\/jats:italic>\n                      in\u00a0vitro. Luciferase reporter gene assay and ChIP assay were performed to explore the molecular mechanism of Klf9 action.\n                      <jats:italic>Klf9<\/jats:italic>\n                      <jats:sup>mlc\u2212\/\u2212<\/jats:sup>\n                      and\n                      <jats:italic>Klf9<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice were treated with dexamethasone (Dex). Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the Dex\/Klf9\u2010ediated skeletal muscle wasting.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Skeletal muscle\n                      <jats:italic>Klf9<\/jats:italic>\n                      gene expression was significantly upregulated by Dex (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05 or\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01 vs. vehicle group). Compared with littermate control mice (R\u2010loxP), m\n                      <jats:italic>Klf9<\/jats:italic>\n                      TG mice exhibited decreased skeletal muscle mass (TA 0.101\u2009\u00b1\u20090.018 vs. 0.040\u2009\u00b1\u20090.007\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and impaired grip strength (forelimb 157.4\u2009\u00b1\u20093.7 vs. 93.45\u2009\u00b1\u20099.8 and four limbs 255.3\u2009\u00b1\u200923.1 vs. 170.1\u2009\u00b1\u200936.2,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Conversely, compared with\n                      <jats:italic>Klf9<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      ,\n                      <jats:italic>Klf9<\/jats:italic>\n                      <jats:sup>mlc\u2212\/\u2212<\/jats:sup>\n                      mice exhibited increased skeletal muscle mass (TA 0.103\u2009\u00b1\u20090.012 vs. 0.123\u2009\u00b1\u20090.005\u2009g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and enhanced grip strength (forelimb 110.3\u2009\u00b1\u20095.8 vs. 156.8\u2009\u00b1\u200910.0 and four limbs 155.5\u2009\u00b1\u20096.3 vs. 226.5\u2009\u00b1\u200919.7,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Skeletal muscle Klf9 deficiency alleviated muscle atrophy induced by acute high\u2010dose Dex treatment (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Mechanistically, Klf9 induces the expression of myostatin (Mstn) and muscle atrophy F\u2010box (MAFbx) by directly binding to and activating the transcription of their promoters. Treatment of AAV\u2010MSTN reduced the increased grip strength of\n                      <jats:italic>Klf9<\/jats:italic>\n                      <jats:sup>mlc\u2212\/\u2212<\/jats:sup>\n                      mice (forelimb 143.5\u2009\u00b1\u200922.3 vs. 118.8\u2009\u00b1\u20093.1 and four limbs 249.8\u2009\u00b1\u200924.7 vs. 208.7\u2009\u00b1\u20099.0,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In summary, our study provides novel insights into the mechanisms underlying GC\u2010induced muscular atrophy and reveals that skeletal muscle induction of Klf9 expression is a mechanism underlying GC therapy\u2010induced muscle loss. Thus, targeting Klf9 may offer novel approaches to the treatment of skeletal muscle wasting diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70020","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T07:30:20Z","timestamp":1753687820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Klf9 Loss of Function Protects Against Glucocorticoids Induced Skeletal Muscle Wasting"],"prefix":"10.1002","volume":"16","author":[{"given":"Yujie","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingran","family":"Hao","sequence":"additional","affiliation":[{"name":"Key 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