{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:50:52Z","timestamp":1787503852609,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T00:00:00Z","timestamp":1706140800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012456","name":"National Social Science Fund of China","doi-asserted-by":"publisher","award":["32071116"],"award-info":[{"award-number":["32071116"]}],"id":[{"id":"10.13039\/501100012456","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012456","name":"National Social Science Fund of China","doi-asserted-by":"publisher","award":["82270449"],"award-info":[{"award-number":["82270449"]}],"id":[{"id":"10.13039\/501100012456","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012456","name":"National Social Science Fund of China","doi-asserted-by":"publisher","award":["82070300"],"award-info":[{"award-number":["82070300"]}],"id":[{"id":"10.13039\/501100012456","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012456","name":"National Social Science Fund of China","doi-asserted-by":"publisher","award":["82270493"],"award-info":[{"award-number":["82270493"]}],"id":[{"id":"10.13039\/501100012456","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012456","name":"National Social Science Fund of China","doi-asserted-by":"publisher","award":["82070875"],"award-info":[{"award-number":["82070875"]}],"id":[{"id":"10.13039\/501100012456","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":[[2024,4]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n CREG1 (cellular repressor of E1A\u2010stimulated genes 1) is a protein involved in cellular differentiation and homeostasis regulation. However, its role in skeletal muscle satellite cells differentiation and muscle regeneration is poorly understood. This study aimed to investigate the role of CREG1 in myogenesis and muscle regeneration.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n RNA sequencing data (GSE8479) was analysed from the Gene Expression Omnibus database (GEO,\n https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi<\/jats:ext-link>\n ). We generated\n Creg1<\/jats:italic>\n knockdown and skeletal muscle satellite cells specific\n Creg1<\/jats:italic>\n overexpression mice mediated by adeno\u2010associated virus serotype 9 (AAV9), skeletal muscle mature myofibre\n Creg1<\/jats:italic>\n knockout mice (myoblast\/\n Creg1MKO<\/jats:italic>\n ), and control mice\n Creg1<\/jats:italic>\n \n flox\/flox<\/jats:italic>\n <\/jats:sup>\n (\n Creg1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n ) as in vivo models. The mice were injected into tibialis anterior (TA) muscle with 100\u00a0\u03bcL of 10\u00a0\u03bcM cardiotoxin to establish a muscle regeneration model.\n Creg1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n and\n Creg1MKO<\/jats:italic>\n mice were treated with AAV\u2010sh\u2010C\u2010Cbl (2\u00a0\u00d7\u00a010\n 10<\/jats:sup>\n genomic copies\/mouse) to silence\n C\u2010Cbl<\/jats:italic>\n in the TA muscle. 293T and C2C12 cells were transfected with plasmids using lipofectamine RNAi MAX in vitro. Mass spectrometry analyses and RNA sequencing transcriptomic assay were performed.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We analysed the transcriptional profiles of the skeletal muscle biopsies from healthy older (\n N<\/jats:italic>\n \u00a0=\u00a025) and younger (\n N<\/jats:italic>\n \u00a0=\u00a026) adult men and women in GSE8479 database, and the results showed that\n Creg1<\/jats:italic>\n was associated with human sarcopenia. We found that\n Creg1<\/jats:italic>\n knockdown mice regenerated less newly formed fibres in response to cardiotoxin injection (~30% reduction,\n P<\/jats:italic>\n \u00a0<\u00a00.01); however, muscle satellite cells specific\n Creg1<\/jats:italic>\n overexpression mice regenerated more newly formed fibres (~20% increase,\n P<\/jats:italic>\n \u00a0<\u00a00.05). AMPKa1 is known as a key mediator in the muscle regeneration process. Our results revealed that CREG1 deficiency inhibited AMPKa1 signalling through C\u2010CBL E3\u2010ubiquitin ligase\u2010mediated AMPKa1 degradation (\n P<\/jats:italic>\n \u00a0<\u00a00.01). C\u2010CBL\u2010mediated AMPKa1 ubiquitination was attributed to the K48\u2010linked polyubiquitination of AMPKa1 at K396 and that the modification played an important role in the regulation of AMPKa1 protein stability. We also found that\n Creg1MKO<\/jats:italic>\n mice regenerated less newly formed fibres compared with\n Creg1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n mice (~30% reduction,\n P<\/jats:italic>\n \u00a0<\u00a00.01). RNA\u2010seq analysis showed that CREG1 deletion in impaired muscles led to the upregulation of inflammation and DKK3 expression. The TA muscles of\n Creg1MKO<\/jats:italic>\n mice were injected with AAV\u2010vector or AAV\u2010shC\u2010Cbl, silencing C\u2010CBL (\n P<\/jats:italic>\n \u00a0<\u00a00.01) in the skeletal muscles of\n Creg1MKO<\/jats:italic>\n mice significantly improved muscle regeneration induced by CTX injury (\n P<\/jats:italic>\n \u00a0<\u00a00.01).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Our findings suggest that CREG1 may be a potential therapeutic target for skeletal muscle regeneration.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.13427","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T22:55:23Z","timestamp":1706223323000},"page":"587-602","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["CREG1 deficiency impaired myoblast differentiation and skeletal muscle regeneration"],"prefix":"10.1002","volume":"15","author":[{"given":"Haixu","family":"Song","sequence":"first","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute, State Key Laboratory of Frigid Zone Cardiovascular Disease General Hospital of Northern Theater Command Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiang","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute, State Key Laboratory of Frigid Zone Cardiovascular Disease General Hospital of Northern Theater Command Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianqi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute, State Key Laboratory of Frigid Zone Cardiovascular Disease General Hospital of Northern Theater Command Shenyang 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