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Published on: November 30, 2016
RAGE Re-Expressed at Myofibre Level Drives Muscle Wasting in Cancer Conditions.
Sara Chiappalupi1,2,3, Giulia Gentili1,2,3, Laura Salvadori2,4
1Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Journal of Cachexia, Sarcopenia and Muscle
|May 9, 2026
Summary
Targeting the receptor for advanced glycation end-products (RAGE) in muscle cells can prevent cancer cachexia (CC). Ablating RAGE in muscle protects against weight loss and inflammation, offering a potential therapeutic strategy for cancer patients.
Area of Science:
- Biomedical Science
- Oncology
- Molecular Biology
Background:
- Cancer cachexia (CC) is a severe wasting syndrome in advanced cancer patients, characterized by significant body and muscle mass loss.
- The receptor for advanced glycation end-products (RAGE) is implicated in inflammatory responses and its total absence restrains CC in mice.
- RAGE is re-expressed in atrophying muscle fibers during cancer, but its specific role in muscle was unclear.
Purpose of the Study:
- To investigate the specific contribution of muscle RAGE to cancer cachexia.
- To determine if selective RAGE ablation in myofibers can prevent or mitigate CC.
- To explore the molecular mechanisms underlying RAGE's role in muscle wasting.
Main Methods:
- Generated a tamoxifen-inducible conditional mouse model (AgermKO) for selective RAGE ablation in myofibers.
- Administered Lewis lung carcinoma (LLC) cells to AgermKO, Agerflox, and Ager-/- mice, monitoring body weight, survival, and performing histological, molecular, and proteomic analyses.
- Analyzed muscle samples from pre-cachectic and cachectic cancer patients to validate findings.
Main Results:
- Mice with muscle-specific RAGE ablation (LLC-AgermKO) exhibited reduced body weight loss, preserved muscle mass and strength, and increased survival compared to controls.
- Muscle RAGE ablation maintained the Akt-GSK-3β-PGC-1α pathway, increased myosin heavy chain synthesis, and promoted myofiber remodeling.
- Cachectic patient muscles showed increased RAGE expression and a downregulated Akt-GSK-3β-PGC-1α pathway, correlating with RAGE's role in CC onset.
Conclusions:
- RAGE signaling in myofibers drives body and muscle weight loss and inflammation in cancer.
- Muscle RAGE ablation confers resistance to cancer cachexia via myofiber remodeling and metabolic reprogramming.
- Overexpression of RAGE in cancer patients' muscles is an early event, suggesting RAGE as a therapeutic target to combat cachexia and improve survival.
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