title: Muscle-specific E3 ubiquitin ligases are involved in muscle atrophy of cancer cachexia: an in vitro and in vivo study.
abstract: Muscle atrophy F-Box (MAFbx)/atrogin-1 and muscle ring-finger-1 (MuRF-1) have been identified as two muscle-specific E3 ubiquitin ligases that are highly expressed in skeletal muscle during muscle atrophy. However, the role of muscle-specific E3 ubiquitin ligases during the process of muscle atrophy of cancer cachexia remains largely unknown. In the present study, we analyzed the expression of atrogin-1 and MuRF-1 in the skeletal muscle of patients with malignant and benign disease. The possible mechanisms were studied both in a colon 26-induced cancer cachexia mouse model and in tumor necrosis factor-α (TNF-α) induced atrophy C2C12 cells. Our results demonstrated that atrogin-1 and MuRF-1 tended to be increased in the skeletal muscle of patients with malignant disease even before weight loss. Non-tumor body weights and gastrocnemius weights were significantly decreased while expression levels of ubiquitin proteasome pathway associated genes (atrogin-1, MuRF-1, ubiquitin and E2-14K) were upregulated in cancer cachexia mice. Significant myotube atrophy with atrogin-1 overexpression was observed in the C2C12 cells treated with TNF-α. Meanwhile, knockdown of atrogin-1 by small interfering RNA (siRNA) protected C2C12 cells from the adverse effect of TNF-α. In conclusion, muscle-specific E3 ubiquitin ligases were upregulated during cancer cachexia, and atrogin-1 may be a potential molecular target for treating muscle atrophy induced by cancer cachexia.
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Qiulei
authors.initials: Q
authors.lastname: Xi
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Qiulin
authors.initials: Q
authors.lastname: Zhuang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Yusong
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Guohao
authors.initials: G
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002100:Cachexia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C440907:FBXO32 protein, human; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases