{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:50:00Z","timestamp":1790880600707,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,1,30]],"date-time":"2022-01-30T00:00:00Z","timestamp":1643500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cachexia is a complicated metabolic disorder that is characterize by progressive atrophy of skeletal muscle. Cathepsin K (CTSK) is a widely expressed cysteine protease that has garnered attention because of its enzymatic and non\u2010enzymatic functions in signalling in various pathological conditions. Here, we examined whether CTSK participates in cancer\u2010induced skeletal muscle loss and dysfunction, focusing on protein metabolic imbalance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male 9\u2010week\u2010old wild\u2010type (CTSK<jats:sup>+\/+<\/jats:sup>, <jats:italic>n<\/jats:italic>\u00a0=\u00a010) and CTSK\u2010knockout (CTSK<jats:sup>\u2212\/\u2212<\/jats:sup>, <jats:italic>n<\/jats:italic>\u00a0=\u00a010) mice were injected subcutaneously with Lewis lung carcinoma cells (LLC; 5\u00a0\u00d7\u00a010<jats:sup>5<\/jats:sup>) or saline, respectively. The mice were then subjected to muscle mass and muscle function measurements. HE staining, immunostaining, quantitative polymerase chain reaction, enzyme\u2010linked immunosorbent assay, and western blotting were used to explore the CTSK expression and IRS1\/Akt pathway in the gastrocnemius muscle at various time points. <jats:italic>In vitro<\/jats:italic> measurements included CTSK expression, IRS1\/Akt pathway\u2010related target molecule expressions, and the diameter of C2C12 myotubes with or without LLC\u2010conditioned medium (LCM). An IRS1 ubiquitin assay, and truncation, co\u2010immunoprecipitation, and co\u2010localization experiments were also performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CTSK<jats:sup>+\/+<\/jats:sup> cachectic animals exhibited loss of skeletal muscle mass (muscle weight loss of 15%, <jats:italic>n<\/jats:italic>\u00a0=\u00a010, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), muscle dysfunction (grip strength loss\u00a0&gt;\u00a015%, <jats:italic>n<\/jats:italic>\u00a0=\u00a010, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), and fibre area (average area reduction\u00a0&gt;\u00a030%, <jats:italic>n<\/jats:italic>\u00a0=\u00a05, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Compared with that of non\u2010cachectic CTSK<jats:sup>+\/+<\/jats:sup> mice, the skeletal muscle of cachectic CTSK<jats:sup>+\/+<\/jats:sup> mice exhibited greater degradation of insulin receptor substrate 1 (IRS1, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). In this setting, cachectic muscles exhibited decreases in the phosphorylation levels of protein kinase B (Akt<jats:sup>308<\/jats:sup>, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; Akt<jats:sup>473<\/jats:sup>, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and anabolic\u2010related proteins (the mammalian target of rapamycin, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and increased levels of catabolism\u2010related proteins (muscle RING\u2010finger protein\u20101, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; MAFbx1, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) in CTSK<jats:sup>+\/+<\/jats:sup> mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a03). Although there was no difference in LLC tumour growth (<jats:italic>n<\/jats:italic>\u00a0=\u00a010, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.44), CTSK deletion mitigated the IRS1 degradation, loss of the skeletal muscle mass (<jats:italic>n<\/jats:italic>\u00a0=\u00a010, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), and dysfunction (<jats:italic>n<\/jats:italic>\u00a0=\u00a010, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). <jats:italic>In vitro<\/jats:italic>, CTSK silencing prevented the IRS1 ubiquitination and loss of the myotube myosin heavy chain content (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) induced by LCM, and these changes were accelerated by CTSK overexpression even without LCM. Immunoprecipitation showed that CTSK selectively acted on IRS1 in the region of amino acids 268 to 574. The results of co\u2010transfection of IRS1\u2010N\u2010FLAG or IRS1\u2010C\u2010FLAG with CTSK suggested that CTSK selectively cleaves IRS1 and causes ubiquitination\u2010related degradation of IRS1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results demonstrate that CTSK plays a novel role in IRS1 ubiquitination in LLC\u2010induced muscle wasting, and suggest that CTSK could be an effective therapeutic target for cancer\u2010related cachexia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12919","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T03:34:12Z","timestamp":1643600052000},"page":"1197-1209","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Cathepsin K activity controls cachexia\u2010induced muscle atrophy via the modulation of IRS1 ubiquitination"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiangkun","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Community Healthcare &amp; Geriatrics Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Hypertension Yanbian University Hospital  Yanji China"},{"name":"Department of Human Cord Stem Cell Therapy, Graduate School of Medicine Nagoya University  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiko","family":"Inoue","sequence":"additional","affiliation":[{"name":"Institute of Innovation for Future Society Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Community Healthcare &amp; Geriatrics Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Community Healthcare &amp; Geriatrics Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueling","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Community Healthcare &amp; Geriatrics Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Community Healthcare &amp; Geriatrics Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Community Healthcare &amp; Geriatrics Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010Ping","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Kuzuya","sequence":"additional","affiliation":[{"name":"Department of Community Healthcare &amp; Geriatrics Nagoya University Graduate School of Medicine  Nagoya Japan"},{"name":"Institute of Innovation for Future Society Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9758-0632","authenticated-orcid":false,"given":"Xian Wu","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Hypertension Yanbian University Hospital  Yanji China"},{"name":"Department of Human Cord Stem Cell Therapy, Graduate School of Medicine Nagoya University  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,1,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70218-7"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.105"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2009-0153"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/SPC.0000000000000301"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(08)70153-0"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13539-014-0164-8"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4467"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2012.209"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116897"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-018-0657-0"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12354"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00073.2004"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.004"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202001330R"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.0394"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12248"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.1988.01400260105013"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2015.08.010"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2003.18.2.222"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12018-011-9093-7"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0727-2"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09037-z"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0350"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.172320"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7254.2008.00889.x"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi025638x"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-018-0153-0"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2018.09.021"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.292"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-007-0177-2"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1101-1014"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9091970"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01347-08"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.09.011"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25146"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/372186a0"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/372182a0"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(96)03875-0"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251541198"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200903131"},{"key":"e_1_2_7_42_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.12919","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.12919","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.12919","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T16:33:04Z","timestamp":1692981184000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.12919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,30]]},"references-count":41,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1002\/jcsm.12919"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.12919","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,30]]},"assertion":[{"value":"2021-05-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}