RAGE Re-Expressed at Myofibre Level Drives Muscle Wasting in Cancer Conditions
Abstract
Background: Cancer cachexia (CC) is a highly debilitating syndrome characterized by loss of body and muscle weight affecting most advanced cancer patients. The receptor for advanced glycation end-products (RAGE) is expressed by several cell types and sustains the inflammatory response in acute and chronic diseases. Total ablation of RAGE (Ager-/- mice) translates into restrained CC and increased survival in tumour-bearing mice. RAGE, which is not expressed in adult healthy myofibres, is re-expressed in atrophying myofibres in cancer conditions. However, the specific contribution of muscular RAGE to CC was unknown.
Methods: Using an HSA/Cre-loxP system, we generated a tamoxifen-inducible conditional AgermKO mouse model in which RAGE is selectively ablated in myofibres. Tamoxifen-treated AgermKO, Agerflox and Ager-/- mice were subcutaneously injected with Lewis lung carcinoma (LLC) cells, and body changes and survival were monitored until 25 dpi, when histological, molecular and proteomic analyses were performed in tumour-bearing and control mice. Muscle samples of pre-cachectic and cachectic pancreatic cancer patients were analysed to validate the results.
Results: Compared with LLC-Agerflox mice, LLC-AgermKO mice showed reduced (7.5% [p = 0.004] vs. 15.1% [p mKO muscles resist cancer-induced atrophy by maintaining an active Akt-GSK-3β-PGC-1α pathway, and increasing the synthesis of myosin heavy chain (MyHC)-I and -IIa (71.8% [p = 0.008] and 73.9% [p = 0.002] increase,…
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