Integrative analysis of inhibition of advanced glycation end-products accumulation and prevention of aging muscle deterioration in animals and human models

Abstract

Background: Advanced glycation end-products (AGEs) contribute to metabolic dysfunction and sarcopenia by promoting oxidative stress and inflammation. The therapeutic impact of exercise on AGEs-induced muscle deterioration and clinical relevance of skin autofluorescence (SAF) as a biomarker remain unclear. Therefore, we aimed to comprehensively investigate the physiological effects of AGEs using two complementary approaches. Methods: This study comprised an animal experiment and a human observational study. In Experiment 1, male mice were administered methylglyoxal (MGO) to induce muscle atrophy and treated with or without treadmill exercise for 12 weeks. Muscle morphology, function, and atrophy-related markers were evaluated. In Experiment 2, 37 older adults (≥65 years) were stratified into low-SAF (<2.3 arbitrary units [AU]) and high-SAF (>2.7 AU) groups. Nε-(carboxymethyl)lysine (CML) and secreted protein acidic and rich in cysteine (SPARC) levels were compared. Results: In mice, muscle atrophy induced by MGO was associated with upregulation of MuRF1 and Atrogin-1, increased fibrosis, and suppression of MyoD and myogenin proteins. Aerobic exercise prevented these effects, restoring muscle mass, enhancing glucose transporter type 4 and myosin heavy chain expression, and reducing SMAD2/3 signaling. In humans, the high-SAF group showed elevated insulin resistance, higher CML, reduced SPARC, and poor performance in grip strength, five times sit-to-stand (STS), 2-min walk test, and STS power. SAF positively correlated with CML and negatively with muscle function. Conclusions: Aerobic exercise mitigates AGEs-induced muscle deterioration through molecular and structural improvements. SAF and CML may serve as noninvasive biomarkers of functional decline in older adults. These findings highlight the potential of exercise to counteract sarcopenia associated with AGEs accumulation.