43 | Synergistic negative effects of advanced glycation end products and tumor-conditioned medium on C2C12 myotubes and the protective activity of Vaccinium macrocarpon

T. Raiteri², Hajar Meskine¹, L. Salvadori¹, M. Paiella², F. Prodam³, F. Riuzzi², N. Filigheddu¹ | ¹Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; ²Department of Medicine and Surgery, University of Perugia, Perugia, Italy; ³Department of Health Science, University of Piemonte Orientale, Novara, Italy.

Cancer cachexia (CC) is a complex and multifactorial syndrome characterized by progressive loss of skeletal muscle mass that could be worsened by unhealthy dietary habits, such as the consumption of a Western diet (WD), which supplies high quantities of advanced glycation end products (AGEs), non-enzymatic adducts formed through the reaction of reducing sugars with cellular macromolecules that can can alter the structure and function of the latter. An excessive accumulation of AGEs has been observed in both the plasma and tumor microenvironment of cancer patients, where it correlates with the severity of muscle wasting. In recent years, natural compounds have emerged as promising candidates for treatment due to their diverse bioactive properties. Among these, Vaccinium macrocarpon (VM) has been identified through preliminary ad hoc screening as a potent inhibitor of AGE formation and activity, suggesting its potential as a therapeutic agent against AGE-induced muscle wasting. Since the degeneration of the neuromuscular junction (NMJ) may contribute to CC-related muscle wasting, we explored the role of AGEs in the dismantling on NMJ and the therapeutic potential effect of VM, with a particular focus the effects on AChR formation and clustering, a well-established in vitro model for evaluating NMJ development and function. Our data indicate that AGEs cause the worsening of atrophy of C2C12 myotubes and a reduction of AChR clustering (an in vitro model of NMJ formation) induced by the treatment of cells with Lewis lung carcinoma conditioned medium (LLC-CM). Co-treatment with VM rescued myotube diameter and AChR clustering, suggesting its potential to mitigate the detrimental effects on skeletal muscle of WD associated with CC.