Engagement of the receptor RAGE at myofiber level is a determinant for muscle wasting in cancer conditions

ABSTRACT: Cachexia is a highly debilitating multifactorial syndrome affecting more than 50% of patients with advanced cancer. RAGE (receptor for advanced glycation end-products) signaling in mice sustains hallmarks of cancer cachexia (CC), including inflammation, the release of tumor-derived CC factors, and skeletal muscle catabolism. Indeed, mice lacking RAGE (Ager−/− mice) showed delayed loss of muscle mass and strength and dramatically increased survival. Here, we investigated the specific contribution to CC of RAGE expressed at tumor and muscle level by using: i) WT and Ager−/− mice subcutaneously injected with LLC (Lewis lung carcinoma) cell clones stably transfected with full-length (fl) RAGE, RAGEΔcyto (a non-transducing form of RAGE) or empty vector; and, ii) a newly generated tamoxifen-inducible conditional AgermKO mouse model, in which the RAGE gene is selectively deleted in skeletal muscles, injected with LLC cells. We found that: i) modulation of RAGE expression in LLC clones did not alter their cachectic potential; ii) Ager−/− mice did not activate muscle catabolism irrespective of the injected LLC clone, suggesting that RAGE overexpression in the tumor is not sufficient per se to induce muscle atrophy; and, iii) LLC-injected AgermKO mice showed increased survival, maintenance of muscle performance, resistance to the loss of body, muscle mass and performance, and reduced circulating CC factors compared with LLC-bearing control (Agerflox) mice. An increase in hybrid myofibers expressing both slow and fast MyHC isoforms characterized muscles of LLC-AgermKO . Different and unexpected proteomic signatures were found in muscles of tumor-bearing mice in dependence on RAGE expression and thirty-five proteins emerged as modulated in common in LLC/AgermKO and LLC/Ager–/– vs LLC/Agerflox mice suggesting novel mechanisms involved in the resistance against CC. Thus, RAGE engagement at myofiber rather than tumor level is a determinant in sustaining CC. Nevertheless, total ablation of the receptor maximally protects against cancer-induced muscle wasting, indicating that systemic targeting of RAGE might represent a promising strategy to counteract the cachexia syndrome in cancer patients.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Muscle

SUBMITTER: Marcello Manfredi  

LAB HEAD: Marcello Manfredi

PROVIDER: PXD060768 | Pride | 2026-05-04

REPOSITORIES: Pride