CREG1 deficiency impaired myoblast differentiation and skeletal muscle regeneration.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38272853", "kind": "science-record", "revision": 4, "content_hash": "sha256:49b7172f362e51a31cbf7e55c8c8f7f675740f4186e23893795305c4eabc8fbb", "created_at": "2026-11-01T19:20:11Z", "updated_at": "2026-11-01T22:53:32Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "CREG1 deficiency impaired myoblast differentiation and skeletal muscle regeneration.", "doi": "10.1002/jcsm.13427", "pmid": "38272853", "authors": ["Haixu Song", "Xiaoxiang Tian", "Lianqi He", "Dan Liu", "Jiayin Li", "Zhu Mei", "Ting Zhou", "Chunying Liu", "Jiaqi He", "Xiaodong Jia", "Zheming Yang", "Chenghui Yan", "Yaling Han"], "journal": "Journal of cachexia, sarcopenia and muscle", "year": 2024, "abstract": "BACKGROUND: CREG1 (cellular repressor of E1A-stimulated 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.\nMETHODS: RNA sequencing data (GSE8479) was analysed from the Gene Expression Omnibus database (GEO, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi). We generated Creg1 knockdown and skeletal muscle satellite cells specific Creg1 overexpression mice mediated by adeno-associated virus serotype 9 (AAV9), skeletal muscle mature myofibre Creg1 knockout mice (myoblast/Creg1MKO), and control mice Creg1flox/flox (Creg1fl/fl) as in vivo models. The mice were injected into tibialis anterior (TA) muscle with 100 μL of 10 μM cardiotoxin to establish a muscle regeneration model. Creg1fl/fl and Creg1MKO mice were treated with AAV-sh-C-Cbl (2 × 1010 genomic copies/mouse) to silence C-Cbl 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.\nRESULTS: We analysed the transcriptional profiles of the skeletal muscle biopsies from healthy older (N = 25) and younger (N = 26) adult men and women in GSE8479 database, and the results showed that Creg1 was associated with human sarcopenia. We found that Creg1 knockdown mice regenerated less newly formed fibres in response to cardiotoxin injection (~30% reduction, P < 0.01); however, muscle satellite cells specific Creg1 overexpression mice regenerated more newly formed fibres (~20% increase, P < 0.05). AMPKa1 is known as a key mediator in the muscle regeneration process. Our results revealed that CREG1 deficiency inhibited AMPKa1 signalling through C-CBL E3-ubiquitin ligase-mediated AMPKa1 degradation (P < 0.01). C-CBL-mediated AMPKa1 ubiquitination was attributed to the K48-linked polyubiquitination of AMPKa1 at K396 and that the modification played an important role in the regulation of AMPKa1 protein stability. We also found that Creg1MKO mice regenerated less newly formed fibres compared with Creg1fl/fl mice (~30% reduction, P < 0.01). RNA-seq analysis showed that CREG1 deletion in impaired muscles led to the upregulation of inflammation and DKK3 expression. The TA muscles of Creg1MKO mice were injected with AAV-vector or AAV-shC-Cbl, silencing C-CBL (P < 0.01) in the skeletal muscles of Creg1MKO mice significantly improved muscle regeneration induced by CTX injury (P < 0.01).\nCONCLUSIONS: Our findings suggest that CREG1 may be a potential therapeutic target for skeletal muscle regeneration.", "claims": [{"id": "claim-method", "statement": "The Shapiro–Wilk test was used for normality and Levene's test was used for homogeneity of variance. When the data conformed to both normal distribution and homogeneity of variance, differences between the two groups were compared using paired or unpaired t‐tests, one‐way ANOVA, and repeated measures of variance. When the data do not conform to a normal distribution, the method is a non‐parametric test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38272853", "locator": "sections[11] \"Statistical analysis\" paragraph 2", "quote": "The Shapiro–Wilk test was used for normality and Levene's test was used for homogeneity of variance. When the data conformed to both normal distribution and homogeneity of variance, differences between the two groups were compared using paired or unpaired t‐tests, one‐way ANOVA, and repeated measures of variance. When the data do not conform to a normal distribution, the method is a non‐parametric test."}], "state": "complete"}, {"id": "claim-target-result", "statement": "CREG1 deficiency inhibited AMPKa1 signalling through C-CBL E3-ubiquitin ligase-mediated AMPKa1 degradation (P < 0.01).", "kind": "quantitative", "target": {"value": 0.01, "unit": "p-value", "tolerance": null, "source": "Our results revealed that CREG1 deficiency inhibited AMPKa1 signalling through C‐CBL E3‐ubiquitin ligase‐mediated AMPKa1 degradation (P < 0.01)."}, "evidence": [{"asset": "source:pmid:38272853", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "Our results revealed that CREG1 deficiency inhibited AMPKa1 signalling through C‐CBL E3‐ubiquitin ligase‐mediated AMPKa1 degradation (P < 0.01)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "CREG1 deficiency inhibited AMPKa1 signalling through C-CBL E3-ubiquitin ligase-mediated AMPKa1 degradation (P < 0.01).", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:38272853"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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RNA-seq analysis showed that CREG1 deletion in impai", "myogenesis and muscle regeneration. METHODS: RNA sequencing data (GSE8479) was analysed from the Gene Ex", "MAX in vitro. Mass spectrometry analyses and RNA sequencing transcriptomic assay were performed. RESULTS", "ass spectrometry analyses and RNA sequencing transcriptomic assay were performed. RESULTS: We analysed t"], "order_basis": "paper_text_order:396", "id": "assay:1"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["in the TA muscle. 293T and C2C12 cells were transfected with plasmids using lipofectamine RNAi MAX i", "h.gov/geo/query/acc.cgi). We generated Creg1 knockdown and skeletal muscle satellite cells specific", "d with human sarcopenia. We found that Creg1 knockdown mice regenerated less newly formed fibres in", "Methods Experimental animals Creg1 knockdown and skeletal muscle satellite cell specific"], "order_basis": "paper_text_order:555", "id": "assay:2"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["lox/flox (Creg1fl/fl) as in vivo models. The mice were injected into tibialis anterior (TA) muscle", "regeneration model. Creg1fl/fl and Creg1MKO mice were treated with AAV-sh-C-Cbl (2 × 1010 genomic", "DKK3 expression. The TA muscles of Creg1MKO mice were injected with AAV-vector or AAV-shC-Cbl, sil", "control mice Creg1flox/flox (Creg1fl/fl) as in vivo models. 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