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.

The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass

“…Along with their over expression in TNF-α treated C2C12 cells and in a cancer cachexia model in mice, MuRF-1 and MAFbx were recently reported to be up-regulated in skeletal muscles of patients with malignant disease, even before weight loss has occurred [51]. In contrast, the expression of FOXO and that of the muscle specific E3s in skeletal muscle biopsies from patients with upper gastrointestinal cancer was not related with their weight loss [52].…”

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

“…HDAC4 mediates the activation of UPS and autophagy in skeletal muscle upon denervation Skeletal muscle triggers UPS and autophagy to catabolize cellular components in response to denervation [4,43,44]. Since HDAC4 is a crucial mediator of skeletal muscle response to denervation, we monitored the activation of both UPS and autophagy in HDAC4mKO mice, over time.…”

Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer

“…Total proteins were extracted from cells or tissues and quantified by the BCA method (Bio-Rad Laboratories). The western blot analysis was performed as previously described (17). For detection of PFKFB3, we used a rabbit monoclonal anti-PFKFB3 antibody (1:6,000 dilution; Abcam).…”