{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:34:47Z","timestamp":1791488087698,"version":"4.3.4"},"reference-count":39,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102021R1F1A1061445"],"award-info":[{"award-number":["NRF\u20102021R1F1A1061445"]}],"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":[[2025,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Transcriptional intermediary factor 1\u03b3 (TIF1\u03b3) is a negative regulator of TGF\u2010\u03b21 signalling and has been associated with patient survival in renal cell carcinoma. However, its role in diabetes mellitus (DM), particularly in diabetic nephropathy (DN), remains unclear. DN is the leading cause of chronic kidney disease (CKD). We investigated the potential role of TIF1\u03b3 in mitigating multiple DM\u2010related complications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Mice were divided into four groups:\n                      <jats:italic>db<\/jats:italic>\n                      \/m+,\n                      <jats:italic>db\/db<\/jats:italic>\n                      and\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice treated with cytomegalovirus\u2010 or TGF\u2010TIF1\u03b3 plasmids (40\u2009\u03bcg\/mouse; intraperitoneally weekly for 16\u2009weeks). Renal injury, fibrosis, function and gene expression related to fibrosis and epithelial\u2013mesenchymal transition (EMT) in the kidneys were assessed. Muscle atrophy, regeneration markers, myokine levels and exercise capacity were evaluated. C2C12 cells were exposed to palmitate with or without TIF1\u03b3 transfection, and irisin expression and secretion were measured. Muscle\u2010kidney crosstalk was analysed using conditioned media (CM) from TIF1\u03b3\u2010transfected C2C12 cells in palmitate\u2010treated human kidney (HK)\u20102 cells. Additionally, HK\u20102 cells were incubated in CM from fibronectin type III domain\u2010containing protein (FNDC)5\u2010knockdown C2C12 cells to confirm irisin\u2010mediated kidney crosstalk by TIF1\u03b3.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TIF1\u03b3 treatment in\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice resulted in a significant attenuation of renal tubulointerstitial fibrosis (1.5\u2010fold decrease), glomerular injury (1.8\u2010fold improvement), tubular injury (1.6\u2010fold improvement), renal dysfunction (1.7\u2010fold improvement) and a reduction in EMT\u2010related factors (1.8\u2010fold decrease) (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). The levels of administered TIF1\u03b3 plasmids were higher in skeletal muscle than in renal tissues. TIF1\u03b3 expression was significantly elevated in the skeletal muscle of\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice treated with TIF1\u03b3 plasmids (6.5\u2010fold) (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Mice receiving both plasmids exhibited a 1.8\u2010fold reduction in pathological muscle morphology and atrophy\u2010related gene expression, a 3.0\u2010fold increase in regeneration\u2010related gene expression and a 1.6\u2010fold improvement in muscle function (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Irisin expression increased by 2.1\u2010fold in skeletal muscle and serum (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). In TIF1\u03b3\u2010transfected C2C12 cells, irisin secretion was elevated by 1.5\u2010fold (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). CM from TIF1\u03b3\u2010transfected C2C12 cells attenuated EMT in palmitate\u2010treated HK\u20102 cells, compared with medium from nontransfected C2C12 cells (1.9\u2010fold improvement [\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05]). Conversely, FNDC5 knockdown in C2C12 cells accelerated EMT in palmitate\u2010treated HK\u20102 cells, as evidenced by decreased bone morphogenetic protein\u20107 (1.6\u2010fold) and increased EMT\u2010related factors (2.1\u2010fold) (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), compared with palmitate alone and small interfering RNA control.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings emphasize the potential of TIF1\u03b3 as a multitargeted therapeutic agent for DN, mitigating both renal and muscular complications through direct fibrosis inhibition and indirect myokine\u2010mediated inter\u2010organ crosstalk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13810","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T02:36:24Z","timestamp":1745462184000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Transcriptional Intermediary Factor 1\u03b3\u2013Induced Irisin in Skeletal Muscle Attenuates Renal Fibrosis in Diabetic Nephropathy"],"prefix":"10.1002","volume":"16","author":[{"given":"Jin\u00a0Hyun","family":"Kim","sequence":"first","affiliation":[{"name":"Biomedical Research Institute Gyeongsang National University Hospital  Jinju Republic of Korea"},{"name":"Institute of Medical Science Gyeongsang National University  Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seunghye","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine Gyeongsang National University College of Medicine and Gyeongsang National University Hospital  Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hani","family":"Jang","sequence":"additional","affiliation":[{"name":"Institute of Medical Science Gyeongsang National University  Jinju Republic of Korea"},{"name":"Division of Nephrology, Department of Internal Medicine Gyeongsang National University College of Medicine and Gyeongsang National University Hospital  Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sehyun","family":"Jung","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine Gyeongsang National University College of Medicine and Gyeongsang National University Hospital  Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeong\u00a0Hee","family":"Jung","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Gyeongsang National University Hospital  Jinju 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Gyeongsang National University Hospital  Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se\u2010Ho","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Medical Science Gyeongsang National University  Jinju Republic of Korea"},{"name":"Division of Nephrology, Department of Internal Medicine Gyeongsang National University College of Medicine and Gyeongsang National University Hospital  Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun\u00a0Ju","family":"Lee","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Seoul National University Hospital  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo\u2010Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Molecular Medicine &amp; Biopharmaceutical Sciences Seoul National University  Seoul Republic of Korea"},{"name":"Department of Internal Medicine 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