{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T02:01:27Z","timestamp":1775786487470,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:00:00Z","timestamp":1714348800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008546","name":"Diabetesf\u00f6rbundet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008546","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005350","name":"Centrum f\u00f6r idrottsforskning","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005350","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","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":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and exercise depends on regulatory mechanisms that couple structural and metabolic adaptations. The mechanisms that interconnect both processes at the transcriptional level remain underexplored. Nr2f6, a nuclear receptor, regulates metabolism and cell differentiation in peripheral tissues. However, its role in the skeletal muscle is still elusive. Here, we aimed to investigate the effects of Nr2f6 modulation on muscle biology\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Global RNA\u2010seq was performed in Nr2f6 knockdown C2C12 myocytes (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a04\u20135). Molecular and metabolic assays and proliferation experiments were performed using stable Nr2f6 knockdown and Nr2f6 overexpression C2C12 cell lines (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a03\u20136). Nr2f6 content was evaluated in lipid overload models\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a03\u20136).\n                      <jats:italic>In vivo<\/jats:italic>\n                      experiments included Nr2f6 overexpression in mouse\n                      <jats:italic>tibialis anterior<\/jats:italic>\n                      muscle, followed by gene array transcriptomics and molecular assays (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a04),\n                      <jats:italic>ex vivo<\/jats:italic>\n                      contractility experiments (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a05), and histological analysis (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a07). The conservation of Nr2f6 depletion effects was confirmed in primary skeletal muscle cells of humans and mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nr2f6 knockdown upregulated genes associated with muscle differentiation, metabolism, and contraction, while cell cycle\u2010related genes were downregulated. In human skeletal muscle cells, Nr2f6 knockdown significantly increased the expression of myosin heavy chain genes (two\u2010fold to three\u2010fold) and siRNA\u2010mediated depletion of Nr2f6 increased maximal C2C12 myocyte's lipid oxidative capacity by 75% and protected against lipid\u2010induced cell death. Nr2f6 content decreased by 40% in lipid\u2010overloaded myotubes and by 50% in the skeletal muscle of mice fed a high\u2010fat diet. Nr2f6 overexpression in mice resulted in an atrophic and hypoplastic state, characterized by a significant reduction in muscle mass (15%) and myofibre content (18%), followed by an impairment (50%) in force production. These functional phenotypes were accompanied by the establishment of an inflammation\u2010like molecular signature and a decrease in the expression of genes involved in muscle contractility and oxidative metabolism, which was associated with the repression of the uncoupling protein 3 (20%) and PGC\u20101\u03b1 (30%) promoters activity following Nr2f6 overexpression\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Additionally, Nr2f6 regulated core components of the cell division machinery, effectively decoupling muscle cell proliferation from differentiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings reveal a novel role for Nr2f6 as a molecular transducer that plays a crucial role in maintaining the balance between skeletal muscle contractile function and oxidative capacity. These results have significant implications for the development of potential therapeutic strategies for metabolic diseases and myopathies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13480","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T05:55:22Z","timestamp":1714370122000},"page":"1335-1347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3890-2910","authenticated-orcid":false,"given":"Dimitrius Santiago P. S. F.","family":"Guimar\u00e3es","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Structural and Functional Biology University of Campinas  Campinas Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ninon M. F.","family":"Barrios","sequence":"additional","affiliation":[{"name":"Department of Structural and Functional Biology University of Campinas  Campinas Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1831-9792","authenticated-orcid":false,"given":"Andr\u00e9 Gustavo","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Department of Structural and Functional Biology University of Campinas  Campinas Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9379-7543","authenticated-orcid":false,"given":"David","family":"Rizo\u2010Roca","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1191-4791","authenticated-orcid":false,"given":"Maxence","family":"Jollet","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery Karolinska Institutet  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2452-1655","authenticated-orcid":false,"given":"Jonathon A.B.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thiago R.","family":"Araujo","sequence":"additional","affiliation":[{"name":"Department of Structural and Functional Biology University of Campinas  Campinas Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcos Vinicius","family":"da 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