{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:59:38Z","timestamp":1792115978697,"version":"4.4.0"},"reference-count":39,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T00:00:00Z","timestamp":1706140800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2022R1A2C2006318"],"award-info":[{"award-number":["2022R1A2C2006318"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2021R1A6A3A01088095"],"award-info":[{"award-number":["2021R1A6A3A01088095"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2018R1A5A2024425"],"award-info":[{"award-number":["2018R1A5A2024425"]}],"id":[{"id":"10.13039\/501100003725","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":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Fat infiltration in muscle, called \u2018myosteatosis\u2019, precedes muscle atrophy, which subsequently results in sarcopenia. Myosteatosis is frequently observed in patients with nonalcoholic fatty liver disease (NAFLD). We have previously reported that retinoic acid receptor\u2010related orphan receptor\u2010\u03b1 (ROR\u03b1) regulates mitochondrial dynamics and mitophagy in hepatocytes, resulting in an alleviation of NAFLD. In this study, we aimed to investigate the role of ROR\u03b1 in skeletal muscle and to understand molecular mechanisms by which ROR\u03b1 controls mitochondrial capacity, using an NAFLD\u2010associated myosteatosis mouse model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To establish a myosteatosis model, 7\u2010week\u2010old C57BL\/6N mice were fed with high\u2010fat diet (HFD). After 15\u00a0weeks of diet feeding, an adeno\u2010associated virus vector encoding ROR\u03b1 (AAV\u2010ROR\u03b1) was injected to gastrocnemius (GA) muscles, or after 7\u00a0weeks of HFD feeding, JC1\u201040, an ROR\u03b1 agonistic ligand, was administered daily at a dose of 5\u00a0mg\/kg\/day by oral gavage for 5\u00a0weeks. Histological, biochemical and molecular analyses in various in vivo and in vitro experiments were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>First, the number of oxidative MyHC2a fibres with intensive lipid infiltration increased by 3.8\u2010fold in the red region of the GA of mice with myosteatosis (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). ROR\u03b1 was expressed around MyHC2a fibres, and its level increased by 2.7\u2010fold after HFD feeding (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Second, treatment of ROR\u03b1 ligands in C2C12 myoblasts, such as cholesterol sulfate and JC1\u201040, enhanced the number of oxidative fibres stained for MyHC1 and MyHC2a by two\u2010fold to four\u2010fold (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), while it reduced the lipid levels in MyHC2a fibres by 20\u201350% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) in the presence of palmitic acids. Third, mitochondrial membrane potential (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and total area of mitochondria (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) were enhanced by treatment of these ligands. Chromatin immunoprecipitation analysis showed that ROR\u03b1 bound the promoter of GA\u2010binding protein \u03b1 subunit gene that led to activation of mitochondrial transcription factor A (TFAM) in C2C12 myoblasts (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Finally, intramuscular transduction of AAV\u2010ROR\u03b1 alleviated the HFD\u2010induced myosteatosis with fatty atrophy; lipid contents in MyHC2a fibres decreased by 48% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), whereas the number of MyHC2b fibre increased by 22% (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Also, administration of JC1\u201040 improved the signs of myosteatosis in that it decreased the level of adipose differentiation\u2010related protein (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) but increased mitochondrial proteins such as cytochrome <jats:italic>c<\/jats:italic> oxidase 4 and TFAM in GA muscle (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>ROR\u03b1 plays a versatile role in regulating the quantity of mitochondria and the oxidative capacity, ultimately leading to an improvement in myosteatosis symptoms.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13432","type":"journal-article","created":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T03:59:37Z","timestamp":1706241577000},"page":"615-630","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["ROR\u03b1\u2013GABP\u2013TFAM axis alleviates myosteatosis with fatty atrophy through reinforcement of mitochondrial capacity"],"prefix":"10.1002","volume":"15","author":[{"given":"Hyeon\u2010Ji","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy Seoul National University  Seoul South Korea"},{"name":"Research Institute of Pharmaceutical Sciences  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang\u2010Heon","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy Seoul National University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheolhee","family":"Jeong","sequence":"additional","affiliation":[{"name":"College of Pharmacy Seoul National University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong\u2010Hyun","family":"Han","sequence":"additional","affiliation":[{"name":"College of Pharmacy Kangwon National University  Chuncheon South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi\u2010Ock","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy Seoul National University  Seoul South Korea"},{"name":"Research Institute of Pharmaceutical Sciences  Seoul South Korea"},{"name":"Bio\u2010MAX Institute Seoul National University  Seoul South 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