{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:39:03Z","timestamp":1790707143382,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T00:00:00Z","timestamp":1684540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"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\/10\u20101"],"award-info":[{"award-number":["FI 965\/10\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":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis\u2010induced intensive care unit\u2010acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF\u2010\u03b2) is involved in both processes. We uncovered an increased expression of the TGF\u2010\u03b2 receptor II (T\u03b2RII)\u2010inhibitor SPRY domain\u2010containing and SOCS\u2010box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1\u2010mediated inhibition of T\u03b2RII signalling impairs myogenic differentiation in response to inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed gene expression analyses in skeletal muscle of cecal ligation and puncture\u2010 (CLP) and sham\u2010operated mice, as well as\n                      <jats:italic>vastus lateralis<\/jats:italic>\n                      of critically ill and control patients. Pro\u2010inflammatory cytokines and specific pathway inhibitors were used to quantitate\n                      <jats:italic>Spsb1<\/jats:italic>\n                      expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF\u2010\u03b2\/T\u03b2RII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half\u2010life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT\u2010PCR and Western blot analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SPSB1<\/jats:italic>\n                      expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin\u20101\u03b2 (IL\u20101\u03b2), and IL\u20106 increased the\n                      <jats:italic>Spsb1<\/jats:italic>\n                      expression in C2C12 myotubes. TNF\u2010 and IL\u20101\u03b2\u2010induced\n                      <jats:italic>Spsb1<\/jats:italic>\n                      expression was mediated by NF\u2010\u03baB, whereas IL\u20106 increased the\n                      <jats:italic>Spsb1<\/jats:italic>\n                      expression via the glycoprotein 130\/JAK2\/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with T\u03b2RII, resulting in T\u03b2RII ubiquitination and destabilization. SPSB1 impaired T\u03b2RII\u2010Akt\u2010Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (\n                      <jats:italic>Myog<\/jats:italic>\n                      ,\n                      <jats:italic>Mymk<\/jats:italic>\n                      ,\n                      <jats:italic>Mymx<\/jats:italic>\n                      ) and late (\n                      <jats:italic>Myh1<\/jats:italic>\n                      ,\n                      <jats:italic>3<\/jats:italic>\n                      ,\n                      <jats:italic>7<\/jats:italic>\n                      ) differentiation\u2010markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY\u2010 and SOCS\u2010box domains of SPSB1. Co\u2010expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of\n                      <jats:italic>Spsb1<\/jats:italic>\n                      by AAV9\u2010mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Inflammatory cytokines via their respective signalling pathways cause an increase in SPSB1 expression in myocytes and attenuate myogenic differentiation. SPSB1\u2010mediated inhibition of T\u03b2RII\u2010Akt\u2010Myogenin signalling and protein synthesis contributes to a disturbed myocyte homeostasis and myogenic differentiation that occurs during inflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13252","type":"journal-article","created":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T05:00:42Z","timestamp":1684558842000},"page":"1721-1736","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["SPSB1\u2010mediated inhibition of TGF\u2010\u03b2 receptor\u2010II impairs myogenesis in inflammation"],"prefix":"10.1002","volume":"14","author":[{"given":"Yi","family":"Li","sequence":"first","affiliation":[{"name":"Experimental and Clinical Research Center (ECRC), Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin Max Delbr\u00fcck Center (MDC) for Molecular Medicine in the Helmholtz Association  Berlin Germany"},{"name":"DZHK (German Center for Cardiovascular Research), partner site Greifswald  Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"D\u00f6rmann","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), partner site Greifswald  Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Brinschwitz","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), partner site Greifswald  Greifswald 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 (MDC) for Molecular Medicine in the Helmholtz Association  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Martin","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), partner site Greifswald  Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Bartels","sequence":"additional","affiliation":[{"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"}]},{"given":"Ning","family":"Li","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular Research), partner site Greifswald  Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka Voori","family":"Giri","sequence":"additional","affiliation":[{"name":"DZHK (German Center for Cardiovascular 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta","family":"Fielitz","sequence":"additional","affiliation":[{"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"}]},{"given":"Tobias","family":"Wollersheim","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin Humboldt\u2010Universit\u00e4t zu Berlin and Berlin Institute of Health  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius","family":"Grunow","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin Humboldt\u2010Universit\u00e4t zu Berlin and Berlin Institute of Health  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan B.","family":"Felix","sequence":"additional","affiliation":[{"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"}]},{"given":"Steffen","family":"Weber\u2010Carstens","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin Humboldt\u2010Universit\u00e4t zu Berlin and Berlin Institute of Health  Berlin 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 (MDC) for Molecular Medicine in the Helmholtz Association  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver J.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III University of Kiel  Kiel Germany"},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Hamburg\/Kiel\/L\u00fcbeck  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 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