42 | RAGE-ablated skeletal muscles resist cancer-induced atrophy through Akt-GSK-3β-PGC-1α pathway and fast-to-slow myofiber transition

Giulia Gentili^1|2, S. Chiappalupi^1|2, L. Salvadori^1|3, M. Paiella^1|2, K. Mangar⁴, A.M. Schmidt⁴, M. Muscaritoli⁵, F. Riuzzi^1|2, G. Sorci^1|2 | ¹Department of Medicine and Surgery, University of Perugia, Perugia, Italy; ²Interuniversity Institute of Myology (IIM), Perugia, Italy; ³Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; ⁴Department of Medicine, NYU Grossman School of Medicine, New York, USA; ⁵Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy; Giulia Gentili and S. Chiappalupi contributed equally; F. Riuzzi and G. Sorci Shared Senior authorship.

Cancer cachexia (CC) syndrome affects most patients with advanced cancer and is characterized by loss of body weight and muscle atrophy, leading to progressive functional impairment and reduced survival. The receptor for advanced glycation end-products (RAGE) is a multiligand receptor expressed during muscle development but repressed in adult healthy muscles. RAGE is re-expressed at myofiber level in tumor-bearing mice [2], but the specific contribution of muscular RAGE to CC was unknown. Using an HSA/Cre-Lox tamoxifen-inducible conditional AgermKO mouse model, in which RAGE is selectively ablated in myofibers, we demonstrated that, compared with control (Agerflox) mice, AgermKO mice showed reduced body and muscle weight loss, no significant reduction of myofiber cross-sectional areas and muscle functionality, restrained muscle and systemic inflammation, and increased survival, 25 days after s.c. injection of Lewis lung carcinoma (LLC) cells. Mechanistically, AgermKO muscles resist cancer-induced atrophy by maintaining an active Akt-GSK-3β-PGC-1α pathway and promoting a fast-to-slow myofiber transition. Western blotting analysis showed that RAGE is strongly re-expressed in rectus abdominis muscles derived from clinically diagnosed pancreas carcinoma patients, in both the pre-cachectic and cachectic stages, compared with healthy subjects. These data show that the overexpression of RAGE is an early event in skeletal muscles of cancer patients, and suggest an involvement of this receptor in the onset of CC. The results obtained in AgermKO mice indicate that RAGE re-expression and engagement at myofiber level drive muscle wasting and inflammation in cancer conditions. Thus, the molecular targeting of RAGE might represent a useful tool to counteract the cachectic syndrome and prolong survival in cancer patients.