REDD1 deletion attenuates cancer cachexia in mice

Area of Science:

• Muscle wasting disorders
• Cancer biology
• Molecular signaling pathways

Background:

• Cancer cachexia is a wasting disorder causing mortality in advanced cancer patients.
• It involves involuntary weight loss and muscle weakness, impairing physical function.
• Regulated in DNA damage and development 1 (REDD1) is a stress protein upregulated in muscle during wasting, inhibiting mTORC1.

Purpose of the Study:

• To investigate the role of REDD1 in cancer cachexia.
• To determine if REDD1 deletion impacts body weight, lean mass, and muscle atrophy.
• To analyze the effects of REDD1 deletion on Akt/mTORC1 and ubiquitin proteasome pathways.

Main Methods:

• Inoculated wild-type and REDD1 knockout mice with Lewis lung carcinoma (LLC) cells.
• Assessed body weight, lean tissue mass, fat mass, and individual muscle weights.
• Measured myofiber cross-sectional area, Akt/mTORC1 pathway markers (p-Akt, p-4E-BP1), and Foxo3a phosphorylation.

Main Results:

• Wild-type mice showed increased skeletal muscle REDD1 expression and cachexia.
• REDD1 deletion prevented body weight and lean tissue loss, but not fat mass.
• REDD1 knockout mice exhibited attenuated muscle atrophy, maintained Akt/mTORC1 activity, and prevented Foxo3a dephosphorylation.

Conclusions:

• REDD1 plays a significant role in cancer cachexia development.
• REDD1 deletion mitigates skeletal muscle atrophy by preserving protein synthesis and inhibiting protein degradation.
• Targeting REDD1 may be a therapeutic strategy for managing cancer cachexia.