Muscle-specific E3 ubiquitin ligases are involved in muscle atrophy of cancer cachexia: An in vitro and in vivo study

Yuan,Lei; Han,Jun; Meng,Qingyang; Xi,Qiulei; Zhuang,Qiulin; Jiang,Yi; Han,Yusong; Zhang,Bo; Fang,Jing; Wu,Guohao

doi:10.3892/or.2015.3845

Muscle-specific E3 ubiquitin ligases are involved in muscle atrophy of cancer cachexia: An in vitro and in vivo study

Authors:
- Lei Yuan
- Jun Han
- Qingyang Meng
- Qiulei Xi
- Qiulin Zhuang
- Yi Jiang
- Yusong Han
- Bo Zhang
- Jing Fang
- Guohao Wu
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Affiliations: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China, Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China
Published online on: March 9, 2015 https://doi.org/10.3892/or.2015.3845
Pages: 2261-2268

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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.

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