Fighting WESTERN diet-derived AGEs (advanced glycation end products) with natural compounds to mitigate muscle wasting in sarcobesity (WESTERNAGE).

Skeletal muscle has a pivotal role in the maintenance of whole-body metabolism, and the loss of muscle mass and functionality (muscle wasting; MW) predisposes to several diseases. MW is a common feature of noncommunicable chronic diseases (NCDs), such as obesity, diabetes, and sarcopenia, contributing to their deleterious outcomes. Sarcobesity, i.e., MW coincident with increased fat tissue, is a growing, urgent and poorly understood complex syndrome with detrimental consequences and elevated healthcare costs. The nutritional transition to a "Western diet" (WD) increases the development of insulin resistance and metabolic inflexibility predisposing to MW and sarcobesity by sustaining systemic/local inflammation and oxidative stress. WD foods contain high advanced glycation end-products (AGEs), a group of glycosylated adducts also endogenously formed. AGE accumulation over time alters the function of tissue cross-linked proteins and sustains oxidative stress and inflammation via the receptor RAGE. Indeed, AGEs/RAGE interactions have been implicated in multiple metabolic disorders, including obesity, insulin resistance, and diabetes. In RAGE signaling induces MW in several conditions. The mechanisms underlying WD-dependent MW, including the potential role of dietary AGEs (dAGEs)/RAGE axis have not been investigated so far. We hypothesize that high dAGEs might be mediators of WD-dependent MW and contribute to the onset and progression of sarcobesity, predisposing to earlier and more severe metabolic consequences, including type 2 diabetes (T2D). By using in vitro and in vivo preclinical models, and an observational study in patients with obesity and T2D, our project aims to: i) discover and dissect the role of dAGEs/RAGE axis in WD-induced MW; ii) unravel genes, pathways and metabolomic signature affected by WD, thus identifying therapeutic targets for sarcobesity; iii) test anti-dAGEs natural compounds as an approach to maintain muscle mass and functionality, and reduce the risk of comorbidities associated to WD intake; iv) correlate the level of dietary and endogenous AGEs with the severity of sarcopenia; v) identify dAGEs as potential reliable biomarkers of MW risk in patients with obesity and T2D, with high clinical relevance in prevention and early screening of sarcobesity. The synergy between basic science and clinical research will allow the validation in patients of the main findings obtained in preclinical models conferring to the project high translational potential and future socio-economic impact. The already ongoing collaboration between the research units and the consistent collection of preliminary results ensure the project feasibility that will accelerate the identification of strategies to mitigate the detrimental effects of WD and related NCDs in line with the PNRR objectives and WHO agenda goals.