{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T23:03:39Z","timestamp":1776467019864,"version":"3.51.2"},"reference-count":26,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T00:00:00Z","timestamp":1568160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["2R01DK037175\u201032"],"award-info":[{"award-number":["2R01DK037175\u201032"]}],"id":[{"id":"10.13039\/100000002","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":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Muscle wasting from chronic kidney disease (CKD) or from defective insulin signalling results in morbidity and, ultimately, mortality. We have identified an endogenous mediator of insulin resistance, signal regulatory protein alpha (SIRP\u03b1), which leads to cachexia in mice and is associated with cachexia in patients with CKD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed insulin signalling and mechanisms causing muscle atrophy plus white adipose tissue (WAT) metabolism in mouse models of CKD or acute diabetes (streptozotocin treatment). We then examined these factors in mice with global knockout (KO) of SIRP\u03b1 and sought mediators of metabolic responses in muscle and adipose tissues of mice with either muscle\u2010specific or adipose tissue\u2010specific KO of SIRP\u03b1. Metabolic responses were confirmed in primary cultures of adipose cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In mice with CKD, SIRP\u03b1 expression was increased in WAT (three\u2010fold, <jats:italic>P<\/jats:italic> &lt; 0.05), and this was associated with precursors of cachexia: \u2018pathologic browning', thermogenesis, and a two\u2010fold activation of protein kinase A (<jats:italic>P<\/jats:italic> &lt; 0.05 vs. control mice) plus loss of adipose tissue mass. In contrast, mice with SIRP\u03b1 global KO and CKD or acute diabetes experienced improved insulin signalling and activation of pAkt plus \u2018physiologic browning' of WAT. These mice avoided losses of muscle and adipose tissues and experienced a 31% improvement in survival (<jats:italic>P<\/jats:italic> &lt; 0.05) than did wild\u2010type mice with CKD. In muscle\u2010specific SIRP\u03b1 KO mice with CKD, we uncovered that serum SIRP\u03b1 levels (<jats:italic>P<\/jats:italic> &lt; 0.05) were suppressed and were associated with improved insulin signalling both in skeletal muscles and in WAT. These changes were accompanied by physiologic WAT browning. However, in adipose\u2010specific SIRP\u03b1 KO mice with CKD, levels of serum SIRP\u03b1 were increased over two\u2010fold (<jats:italic>P<\/jats:italic> &lt; 0.05), while muscle losses were minimally inhibited. Clinical implications of SIRP\u03b1 signalling are suggested by our findings that include increased SIRP\u03b1 expression in muscle and adipose tissues (<jats:italic>P<\/jats:italic> &lt; 0.05 vs. healthy controls) plus higher SIRP\u03b1 levels in the serum of patients with CKD (2.4\u2010fold, <jats:italic>P<\/jats:italic>=0.000017 vs. healthy controls).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results show that SIRP\u03b1 plays an important role as an anti\u2010insulin mediator regulating pathways to cachexia. In muscle\u2010specific SIRP\u03b1 KO, changes in SIRP\u03b1 serum levels seem to improve insulin signalling in muscle and WAT, suggesting crosstalk between muscle and adipose tissue. Therefore, targeting SIRP\u03b1 may prevent cachexia in patients with CKD or acute diabetes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12459","type":"journal-article","created":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T07:59:15Z","timestamp":1568188755000},"page":"1210-1227","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Signal regulatory protein alpha initiates cachexia through muscle to adipose tissue crosstalk"],"prefix":"10.1002","volume":"10","author":[{"given":"Jiao","family":"Wu","sequence":"first","affiliation":[{"name":"Selzman Institute for Kidney Health, Department of Medicine Baylor College of Medicine  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangling","family":"Dong","sequence":"additional","affiliation":[{"name":"Selzman Institute for Kidney Health, Department of Medicine Baylor College of Medicine  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Verzola","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Medicine Universit\u00e0 degli Studi di Genova  Genoa Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith","family":"Hruska","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Pediatrics Washington University School of Medicine  St. Louis MO USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Garibotto","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Medicine Universit\u00e0 degli Studi di Genova  Genoa Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoyong","family":"Hu","sequence":"additional","affiliation":[{"name":"Selzman Institute for Kidney Health, Department of Medicine Baylor College of Medicine  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William E.","family":"Mitch","sequence":"additional","affiliation":[{"name":"Selzman Institute for Kidney Health, Department of Medicine Baylor College of Medicine  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4993-8812","authenticated-orcid":false,"given":"Sandhya S.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Selzman Institute for Kidney Health, Department of Medicine Baylor College of Medicine  Houston TX USA"},{"name":"Nephrology Division, Department of Medicine Michael E. 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