30 | The advanced glycation end-products (ages)/rage axis drives sarcobesity, which is restrained by Vaccinium macrocarpon extract

Martina Paiella^1|2, L. Salvadori^2|3, T. Raiteri^1|2, G. Gentili^1|2, S. Chiappalupi^1|2, T. Manenti⁴, G. Sorci^1|2, F. Prodam⁵, N. Filigheddu^2|3, F. Riuzzi^1|2 | ¹Dept. Medicine and Surgery, Univ. Perugia, Perugia, Italy; ²Interuniversity Institute of Myology (IIM), Perugia, Italy; ³Dept. Translational Medicine, Univ. Piemonte Orientale, Novara, Italy; ⁴Laboratori Biokyma srl, Anghiari, Italy; ⁵Dept. Health Science, Univ. Piemonte Orientale, Novara, Italy.

Sarcobesity (SO) is a chronic metabolic disorder characterized by ectopic fat deposition (obesity) and concomitant progressive loss of muscle mass and strength (sarcopenia). The diffusion of a Western-like diet (WD) is considered a major risk for SO pathogenesis. WD foods rich in saturated fats and refined sugars contain high amounts of advanced glycation end-products (AGEs), a heterogeneous group of glycated proteins formed via the Maillard reaction. AGEs and their receptor, RAGE, promote ageing and several chronic diseases by sustaining inflammation and oxidative stress. We recently demonstrated that dietary AGEs induce muscle atrophy in vitro, and Vaccinium macrocarpon (VM) extract blunts AGEs. Here, we fed adult WT and RAGE-null (Ager^−/−) mice with high-AGE WD for 20 weeks in the absence or presence of VM. We found AGEs accumulation in muscles and sera of WT mice, in concomitance with muscle RAGE upregulation, loss of muscle performance, reduction of myofiber areas, excessive activation of proteolytic systems, and degradation of the sarcomeric protein, myosin heavy chain (MyHC)-II. Besides muscle, WD-fed WT mice showed hepatomegaly with fat deposition and fibrosis, spleen weight increment and histological alterations, and visceral fat deposition, suggesting the establishment of a chronic low-grade inflammation causing sarcopenia. The ability of VM to abrogate dietary AGE accumulation in muscles and serum of WT mice resulted in rescue of muscle force, downregulated atrogenes and autophagy-related genes, reduced MyHC-II degradation, and restrained WD-dependent body composition changes. Remarkably, WD did not induce sarcopenia in Ager^−/− mice. By in silico target fishing, potential targets of VM’s active metabolites underlying its antiglycation properties were identified. Collectively, our data unravel the AGEs/RAGE axis as a determinant mediator of SO and identify a promising natural strategy for inhibiting dietary AGE-associated sarcopenia.