Li, He, Liu, Dandan, Dong, Huixun, Deng, Xiaoyao, Wang, Lifeng, Zhu, Aihua and Zhou, Shaobo ORCID: https://orcid.org/0000-0001-5214-2973 (2026) MFG-E8-derived antioxidant peptides attenuate dexamethasone-induced skeletal muscle metabolic dysfunction via PI3K/Akt–GLUT4–PPARα signalling pathway. Bioorganic Chemistry:110288. ISSN 0045-2068 (Print), 1090-2120 (Online) (doi:10.1016/j.bioorg.2026.110288)

PDF (Author's Accepted Manuscript) 53996 ZHOU_MFG-E8-Derived_Antioxidant_Peptides_Attenuate_(AAM)_2026.pdf - Accepted Version Restricted to Repository staff only until 25 July 2028. Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (1MB) | Request a copy

Abstract

Oxidative stress and mitochondrial dysfunction are key features of sarcopenia-related skeletal muscle metabolic dysfunction. This study aimed to identify MFG-E8-derived bioactive peptides with antioxidant and metabolic regulatory potential. Integrated bioinformatics analysis highlighted oxidative phosphorylation, thermogenesis, ROS-related pathways and lipid metabolic regulation as major molecular features of sarcopenia-related metabolic dysfunction. After simulated gastrointestinal digestion of bovine milk fat globule epidermal growth factor 8 (MFG-E8), 98 peptides were identified by LC-MS/MS. Candidate peptides were prioritized using peptidomics, ADMET prediction, molecular docking, Caco-2 monolayer-based transepithelial transport assessment and L6 cell-based validation. Among the selected peptides, YAR showed a favorable multi-target docking profile with Akt, PPARα and SIRT1, together with putative transepithelial transport potential in a Caco-2 monolayer model.
and its detection in basolateral fractions after Caco-2 monolayer transport. In dexamethasone-injured L6 myoblasts, YAR displayed the strongest cytoprotective activity, reducing intracellular ROS by up to 52.6%, stabilizing mitochondrial membrane potential, and increasing total Akt and p-Akt fluorescence intensities by 30% and 32%, respectively. YAR also partially restored PI3K/Akt signaling and modulated downstream metabolic effectors, including GLUT4 and PPARα. These findings identify YAR as a promising MFG-E8-derived antioxidant peptide with potential transepithelial transport and cytoprotective activity, providing a mechanistic basis for developing food-derived peptides targeting oxidative stress-related skeletal muscle metabolic dysfunction.

Item Type:	Article
Uncontrolled Keywords:	MFG-E8, peptidomics, oxidative stress, transepithelial transport, L6 myoblasts, PI3K/Akt signaling pathway
Subjects:	Q Science > Q Science (General) Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	03 Aug 2026 14:43
URI:	https://gala.gre.ac.uk/id/eprint/53996

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