{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T06:26:25Z","timestamp":1794464785484,"version":"4.9.1"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017268","name":"Berlin Institute of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FI 965\/9\u20101"],"award-info":[{"award-number":["FI 965\/9\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FI 965\/5\u20102"],"award-info":[{"award-number":["FI 965\/5\u20102"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FI 965\/5\u20101"],"award-info":[{"award-number":["FI 965\/5\u20101"]}],"id":[{"id":"10.13039\/501100001659","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":[[2022,2]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Sepsis and inflammation can cause intensive care unit\u2010acquired weakness (ICUAW). Increased interleukin\u20106 (IL\u20106) plasma levels are a risk factor for ICUAW. IL\u20106 signalling involves the glycoprotein 130 (gp130) receptor and the JAK\/STAT\u2010pathway, but its role in sepsis\u2010induced muscle wasting is uncertain. In a clinical observational study, we found that the IL\u20106 target gene,\n SOCS3<\/jats:italic>\n , was increased in skeletal muscle of ICUAW patients indicative for JAK\/STAT\u2010pathway activation. We tested the hypothesis that the IL\u20106\/gp130\u2010pathway mediates ICUAW muscle atrophy.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We sequenced RNA (RNAseq) from tibialis anterior (TA) muscle of cecal ligation and puncture\u2010operated (CLP) and sham\u2010operated wildtype (WT) mice. The effects of the IL\u20106\/gp130\/JAK2\/STAT3\u2010pathway were investigated by analysing the atrophy phenotype, gene expression, and protein contents of C2C12 myotubes. Mice lacking\n Il6st<\/jats:italic>\n , encoding gp130, in myocytes (cKO) and WT controls, as well as mice treated with the JAK2 inhibitor AG490 or vehicle were exposed to CLP or sham surgery for 24 or 96\u00a0h.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Analyses of differentially expressed genes in RNAseq (\u22652\u2010log2\u2010fold change,\n P<\/jats:italic>\n \u00a0<\u00a00.01) revealed an activation of IL\u20106\u2010signalling and JAK\/STAT\u2010signalling pathways in muscle of septic mice, which occurred after 24\u00a0h and lasted at least for 96\u00a0h during sepsis. IL\u20106 treatment of C2C12 myotubes induced STAT3 phosphorylation (three\u2010fold,\n P<\/jats:italic>\n \u00a0<\u00a00.01) and\n Socs3<\/jats:italic>\n mRNA expression (3.1\u2010fold,\n P<\/jats:italic>\n \u00a0<\u00a00.01) and caused myotube atrophy. Knockdown of\n Il6st<\/jats:italic>\n diminished IL\u20106\u2010induced STAT3 phosphorylation (\u221230.0%;\n P<\/jats:italic>\n \u00a0<\u00a00.01),\n Socs3<\/jats:italic>\n mRNA expression, and myotube atrophy. JAK2 (\u2212 29.0%;\n P<\/jats:italic>\n \u00a0<\u00a00.01) or STAT3 inhibition (\u221238.7%;\n P<\/jats:italic>\n \u00a0<\u00a00.05) decreased IL\u20106\u2010induced\n Socs3<\/jats:italic>\n mRNA expression. Treatment with either inhibitor attenuated myotube atrophy in response to IL\u20106. CLP\u2010operated septic mice showed an increased STAT3 phosphorylation and\n Socs3<\/jats:italic>\n mRNA expression in TA muscle, which was reduced in septic\n Il6st<\/jats:italic>\n \u2010cKO mice by 67.8% (\n P<\/jats:italic>\n \u00a0<\u00a00.05) and 85.6% (\n P<\/jats:italic>\n \u00a0<\u00a00.001), respectively. CLP caused a loss of TA muscle weight, which was attenuated in\n Il6st<\/jats:italic>\n \u2010cKO mice (WT: \u221222.3%,\n P<\/jats:italic>\n \u00a0<\u00a00.001, cKO: \u221213.5%,\n P<\/jats:italic>\n \u00a0<\u00a00.001; WT vs. cKO\n P<\/jats:italic>\n \u00a0<\u00a00.001). While loss of\n Il6st<\/jats:italic>\n resulted in a reduction of MuRF1 protein contents, Atrogin\u20101 remained unchanged between septic WT and cKO mice. mRNA expression of\n Trim63<\/jats:italic>\n \/MuRF1 and\n Fbxo32<\/jats:italic>\n \/Atrogin\u20101 were unaltered between CLP\u2010treated WT and cKO mice. AG490 treatment reduced STAT3 phosphorylation (\u221222.2%,\n P<\/jats:italic>\n \u00a0<\u00a00.05) and attenuated TA muscle atrophy in septic mice (29.6% relative reduction of muscle weight loss,\n P<\/jats:italic>\n \u00a0<\u00a00.05). The reduction in muscle atrophy was accompanied by a reduction in\n Fbxo32<\/jats:italic>\n \/Atrogin\u20101\u2010mRNA (\u221281.3%,\n P<\/jats:italic>\n \u00a0<\u00a00.05) and\n Trim63<\/jats:italic>\n \/MuRF1\u2010mRNA expression (\u221277.6%,\n P<\/jats:italic>\n \u00a0<\u00a00.05) and protein content.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n IL\u20106 via the gp130\/JAK2\/STAT3\u2010pathway mediates sepsis\u2010induced muscle atrophy possibly contributing to ICUAW.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.12867","type":"journal-article","created":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T03:43:22Z","timestamp":1637898202000},"page":"713-727","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":222,"title":["Sepsis induces interleukin 6, gp130\/JAK2\/STAT3, and muscle wasting"],"prefix":"10.1002","volume":"13","author":[{"given":"Lukas","family":"Zanders","sequence":"first","affiliation":[{"name":"Experimental and Clinical Research Center (ECRC) Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany"},{"name":"DZHK (German Center for Cardiovascular Research), partner site Berlin Berlin Germany"},{"name":"Department of Cardiology Charit\u00e9 Campus Benjamin Franklin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Kny","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center (ECRC) Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hahn","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center (ECRC) Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sibylle","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center (ECRC) Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Wundersitz","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center (ECRC) Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihail","family":"Todiras","sequence":"additional","affiliation":[{"name":"Cardiovascular hormones, Max Delbr\u00fcck Center (MDC) for Molecular Medicine in the Helmholtz Association Berlin Germany"},{"name":"Nicolae Testemi\u0163anu State University of Medicine and Pharmacy Chi\u0219in\u0103u Moldova"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Lahmann","sequence":"additional","affiliation":[{"name":"Developmental Biology\/Signal Transduction Max\u2010Delbr\u00fcck\u2010Center for Molecular Medicine Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnab","family":"Bandyopadhyay","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics University Medicine Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Wollersheim","sequence":"additional","affiliation":[{"name":"Anesthesiology and operative Intensive Care Medicine Charit\u00e9 Campus Virchow and Campus Mitte Berlin Germany"},{"name":"Berlin Institute of Health (BIH) Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Kaderali","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics University Medicine Greifswald Greifswald Germany"},{"name":"DZHK (German Center for Cardiovascular Research), partner site Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich C.","family":"Luft","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center (ECRC) Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Birchmeier","sequence":"additional","affiliation":[{"name":"Developmental Biology\/Signal Transduction Max\u2010Delbr\u00fcck\u2010Center for Molecular Medicine Berlin Germany"},{"name":"Berlin Institute of Health (BIH) Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Weber\u2010Carstens","sequence":"additional","affiliation":[{"name":"Anesthesiology and operative Intensive Care Medicine Charit\u00e9 Campus Virchow and Campus Mitte Berlin Germany"},{"name":"Berlin Institute of Health (BIH) Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8522-1045","authenticated-orcid":false,"given":"Jens","family":"Fielitz","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center (ECRC) Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany"},{"name":"Berlin Institute of Health (BIH) Berlin Germany"},{"name":"DZHK (German Center for Cardiovascular Research), partner site Greifswald Greifswald Germany"},{"name":"Department of Internal Medicine B, Cardiology University Medicine Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200712-1829OC"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3181b027e9"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1011802"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-014-3224-9"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.278481"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e31823295e6"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1065874"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc9074"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc9187"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40635-016-0115-0"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0092048"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12491"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3656"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00025.2012"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022538"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00039.2012"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90311-9"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3340297"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.12.015"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200444200"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1101-1009"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9091970"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201209-1649OC"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.10.1955"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12763"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11091327"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-240580"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.641514"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-010-0628-z"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2015.01.045"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/TA.0b013e318164d05f"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1502524"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-017-0527-7"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204833"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00112.2017"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205403200"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a016295"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200304000-00003"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12501"}],"container-title":["Journal of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12867","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.12867","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12867","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T19:55:57Z","timestamp":1692474957000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.12867"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,24]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["10.1002\/jcsm.12867"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.12867","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,24]]},"assertion":[{"value":"2021-07-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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