{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:23:51Z","timestamp":1791476631734,"version":"4.3.4"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["NRF\u20102022R1A2C1007857"],"award-info":[{"award-number":["NRF\u20102022R1A2C1007857"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["NRF\u20102021R1F1A1061393"],"award-info":[{"award-number":["NRF\u20102021R1F1A1061393"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["NRF\u20102020R1C1C1012729"],"award-info":[{"award-number":["NRF\u20102020R1C1C1012729"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["NRF\u20102021R1A5A2021614"],"award-info":[{"award-number":["NRF\u20102021R1A5A2021614"]}],"id":[{"id":"10.13039\/501100014188","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":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Muscle atrophy, leading to muscular dysfunction and weakness, is an adverse outcome of sustained period of glucocorticoids usage. However, the molecular mechanism underlying this detrimental condition is currently unclear. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscle and has been implicated in the pathogenesis of several diseases. The current study was designed to investigated and delineate the role of PDK4 in the context of muscle atrophy, which could be identified as a potential therapeutic avenue to protect against dexamethasone\u2010induced muscle wasting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The dexamethasone\u2010induced muscle atrophy in C2C12 myotubes was evaluated at the molecular level by expression of key genes and proteins involved in myogenesis, using immunoblotting and qPCR analyses. Muscle dysfunction was studied <jats:italic>in vivo<\/jats:italic> in wild\u2010type and PDK4 knockout mice treated with dexamethasone (25\u00a0mg\/kg body weight, i.p., 10\u00a0days). Body weight, grip strength, muscle weight and muscle histology were assessed. The expression of myogenesis markers were analysed using qPCR, immunoblotting and immunoprecipitation. The study was extended to in vitro human skeletal muscle atrophy analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Knockdown of PDK4 was found to prevent glucocorticoid\u2010induced muscle atrophy and dysfunction in C2C12 myotubes, which was indicated by induction of myogenin (0.3271\u00a0\u00b1\u00a00.102 vs 2.163\u00a0\u00b1\u00a00.192, ****<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and myosin heavy chain (0.3901\u00a0\u00b1\u00a00.047 vs. 0.7222\u00a0\u00b1\u00a00.082, **<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) protein levels and reduction of muscle atrophy F\u2010box (10.77\u00a0\u00b1\u00a02.674 vs. 1.518\u00a0\u00b1\u00a00.172, **<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) expression. In dexamethasone\u2010induced muscle atrophy model, mice with genetic ablation of PDK4 revealed increased muscle strength (162.1\u00a0\u00b1\u00a022.75 vs. 200.1\u00a0\u00b1\u00a037.09\u00a0g, ***<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and muscle fibres (54.20\u00a0\u00b1\u00a011.85% vs. 84.07\u00a0\u00b1\u00a028.41%, ****<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001). To explore the mechanism, we performed coimmunoprecipitation and liquid chromatography\u2010mass spectrometry analysis and found that myogenin is novel substrate of PDK4. PDK4 phosphorylates myogenin at S43\/T57 amino acid residues, which facilitates the recruitment of muscle atrophy F\u2010box to myogenin and leads to its subsequent ubiquitination and degradation. Finally, overexpression of non\u2010phosphorylatable myogenin mutant using intramuscular injection prevented dexamethasone\u2010induced muscle atrophy and preserved muscle fibres.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We have demonstrated that PDK4 mediates dexamethasone\u2010induced skeletal muscle atrophy. Mechanistically, PDK4 phosphorylates and degrades myogenin via recruitment of E3 ubiquitin ligase, muscle atrophy F\u2010box. Rescue of muscle regeneration by genetic ablation of PDK4 or overexpression of non\u2010phosphorylatable myogenin mutant indicates PDK4 as an amenable therapeutic target in muscle atrophy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13100","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T04:59:48Z","timestamp":1666155588000},"page":"3122-3136","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Pyruvate dehydrogenase kinase 4 promotes ubiquitin\u2013proteasome system\u2010dependent muscle atrophy"],"prefix":"10.1002","volume":"13","author":[{"given":"Ibotombi Singh","family":"Sinam","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, Graduate School Kyungpook National University  Daegu Republic of Korea"},{"name":"BK21 Plus KNU Biomedical Convergence Program Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipanjan","family":"Chanda","sequence":"additional","affiliation":[{"name":"Research Institute of Aging and Metabolism Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Themis","family":"Thoudam","sequence":"additional","affiliation":[{"name":"Research Institute of Aging and Metabolism Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Ji","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Kyungpook National University Kyungpook National University Hospital  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung\u2010Gyu","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity (CGI), Institute for Basic Science (IBS), Department of Biological Sciences Ulsan National Institute of Science and Technology (UNIST)  Ulsan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeon\u2010Ji","family":"Kang","sequence":"additional","affiliation":[{"name":"Research Institute of Aging and Metabolism Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Yi","family":"Lee","sequence":"additional","affiliation":[{"name":"Leading\u2010edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease Kyungpook National University  Daegu Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung\u2010Hoon","family":"Baek","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, School of Medicine, Kyungpook National University Kyungpook National University Hospital  Daegu South 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