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Volume 14
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10.3390/antiox14080900
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Article

Diet-Derived Advanced Glycation End-Products (AGEs) Induce Muscle Wasting In Vitro, and a Standardized Vaccinium macrocarpon Extract Restrains AGE Formation and AGE-Dependent C2C12 Myotube Atrophy

by
Martina Paiella
1,2,†,
Tommaso Raiteri
2,3,†,
Simone Reano
1,
Dominga Manfredelli
3,
Tommaso Manenti
4,
Giulia Gentili
2,3,
Hajar Meskine
1,
Sara Chiappalupi
2,3,
Giovanni Bellomo
3,
Flavia Prodam
5,
Cinzia Antognelli
3,
Roccaldo Sardella
6,
Anna Migni
6,
Guglielmo Sorci
2,3,
Laura Salvadori
1,2,‡,
Nicoletta Filigheddu
1,2,‡ and
Francesca Riuzzi
2,3,*,‡
1
Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy
2
Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy
3
Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
4
Laboratori Biokyma Srl, 52031 Anghiari, Italy
5
Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy
6
Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors also contributed equally to this work.
Antioxidants 2025, 14(8), 900; https://doi.org/10.3390/antiox14080900
Submission received: 21 May 2025 / Revised: 16 July 2025 / Accepted: 21 July 2025 / Published: 23 July 2025
(This article belongs to the Topic Exploring Nutritional, Antioxidant and Functional Potential of Plant-Based Food and Plant Bioactive Compounds in Human Health)
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Abstract

Dietary advanced glycation end-products (dAGEs) contained in high-sugar/fat and ultra-processed foods of the “Western diet” (WD) pattern predispose to several diseases by altering protein function or increasing oxidative stress and inflammation via RAGE (receptor for advanced glycation end-products). Although elevated endogenous AGEs are associated with loss of muscle mass and functionality (i.e., muscle wasting; MW), the impact of dAGEs on MW has not been elucidated. Here, we show that the most common dAGEs or their precursor, methylglyoxal (MGO), induce C2C12 myotube atrophy as endogenous AGE-derived BSA. ROS production, mitochondrial dysfunction, mitophagy, ubiquitin–proteasome activation, and inhibition of myogenic potential are common atrophying mechanisms used by MGO and AGE-BSA. Although of different origins, ROS are mainly responsible for AGE-induced myotube atrophy. However, while AGE-BSA activates the RAGE-myogenin axis, reduces anabolic mTOR, and causes mitochondrial damage, MGO induces glycolytic stress and STAT3 activation without affecting RAGE expression. Among thirty selected natural compounds, Vaccinium macrocarpon (VM), Camellia sinensis, and chlorophyll showed a surprising ability in counteracting in vitro AGE formation. However, only the standardized VM, containing anti-glycative metabolites as revealed by UHPLC-HRMS analysis, abrogates AGE-induced myotube atrophy. Collectively, our data suggest that WD-linked dAGE consumption predisposes to MW, which might be restricted by VM food supplements.
Keywords: diet-derived AGEs; glycated albumin; RAGE; ROS production; muscle atrophy; natural compounds; mitochondrial function diet-derived AGEs; glycated albumin; RAGE; ROS production; muscle atrophy; natural compounds; mitochondrial function
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MDPI and ACS Style

Paiella, M.; Raiteri, T.; Reano, S.; Manfredelli, D.; Manenti, T.; Gentili, G.; Meskine, H.; Chiappalupi, S.; Bellomo, G.; Prodam, F.; et al. Diet-Derived Advanced Glycation End-Products (AGEs) Induce Muscle Wasting In Vitro, and a Standardized Vaccinium macrocarpon Extract Restrains AGE Formation and AGE-Dependent C2C12 Myotube Atrophy. Antioxidants 2025, 14, 900. https://doi.org/10.3390/antiox14080900

AMA Style

Paiella M, Raiteri T, Reano S, Manfredelli D, Manenti T, Gentili G, Meskine H, Chiappalupi S, Bellomo G, Prodam F, et al. Diet-Derived Advanced Glycation End-Products (AGEs) Induce Muscle Wasting In Vitro, and a Standardized Vaccinium macrocarpon Extract Restrains AGE Formation and AGE-Dependent C2C12 Myotube Atrophy. Antioxidants. 2025; 14(8):900. https://doi.org/10.3390/antiox14080900

Chicago/Turabian Style

Paiella, Martina, Tommaso Raiteri, Simone Reano, Dominga Manfredelli, Tommaso Manenti, Giulia Gentili, Hajar Meskine, Sara Chiappalupi, Giovanni Bellomo, Flavia Prodam, and et al. 2025. "Diet-Derived Advanced Glycation End-Products (AGEs) Induce Muscle Wasting In Vitro, and a Standardized Vaccinium macrocarpon Extract Restrains AGE Formation and AGE-Dependent C2C12 Myotube Atrophy" Antioxidants 14, no. 8: 900. https://doi.org/10.3390/antiox14080900

APA Style

Paiella, M., Raiteri, T., Reano, S., Manfredelli, D., Manenti, T., Gentili, G., Meskine, H., Chiappalupi, S., Bellomo, G., Prodam, F., Antognelli, C., Sardella, R., Migni, A., Sorci, G., Salvadori, L., Filigheddu, N., & Riuzzi, F. (2025). Diet-Derived Advanced Glycation End-Products (AGEs) Induce Muscle Wasting In Vitro, and a Standardized Vaccinium macrocarpon Extract Restrains AGE Formation and AGE-Dependent C2C12 Myotube Atrophy. Antioxidants, 14(8), 900. https://doi.org/10.3390/antiox14080900

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