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: Lei Yuan, Jun Han, Qingyang Meng, Qiulei Xi, Qiulin Zhuang, Yi Jiang, Yusong Han, Bo Zhang, Jing Fang, Guohao Wu
• Journal: Oncology reports (Oncol Rep) Vol. 33 Issue 5 Pg. 2261-8 (May 2015) ISSN: 1791-2431 [Electronic] Greece
• PMID: 25760630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Muscle Proteins
• RNA, Messenger
• Tripartite Motif Proteins
• Tumor Necrosis Factor-alpha
• Ubiquitin
• FBXO32 protein, human
• Fbxo32 protein, mouse
• SKP Cullin F-Box Protein Ligases
• TRIM63 protein, human
• Trim63 protein, mouse
• Ubiquitin-Protein Ligases

Topics

• Adult
• Aged
• Animals
• Cachexia (etiology, genetics, metabolism)
• Case-Control Studies
• Cell Line
• Disease Models, Animal
• Female
• Humans
• In Vitro Techniques
• Male
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Muscle Fibers, Skeletal (drug effects, metabolism)
• Muscle Proteins (genetics, metabolism)
• Muscle, Skeletal (metabolism)
• Muscular Atrophy (etiology, genetics, metabolism)
• Neoplasms (complications, genetics, metabolism)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• SKP Cullin F-Box Protein Ligases (genetics, metabolism)
• Tripartite Motif Proteins
• Tumor Necrosis Factor-alpha (pharmacology)
• Ubiquitin (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)