Stress Inhibits Myogenic Differentiation via Transcriptome Remodeling and GR-Mediated Suppression of the ITGA11-FAK/Paxillin-Akt-GSK3β Cascade

Myogenic differentiation is pivotal for muscle development, yet how stress impairs this process remains inadequately understood. Here, we investigated the dynamic regulatory mechanisms of sheep fetal myoblast (SFM) differentiation under normal and dexamethasone (Dex)-induced stress conditions, focusing on integrin-mediated signaling. Transcriptomic analysis identified multiple differentially expressed genes (DEGs). 153 DEGs exhibited up- or downregulation during differentiation, which was reversed by Dex. They were enriched in ECM-receptor interaction, focal adhesion, and the PI3K-Akt pathway. RU486, a glucocorticoid receptor (GR) antagonist, reversed Dex-induced alterations in key gene and protein expression within the FBLN5/Integrin-FAK/Paxillin-Akt-GSK3β cascade and cell cycle-related pathways. Overexpression/interference experiments confirmed that ITGA11 promoted SFM differentiation and rescued Dex-induced suppression through the FAK/Paxillin-Akt-GSK3β pathway. Taken together, stress inhibits SFM differentiation via the transcriptome remodeling and GR-mediated suppression of the ITGA11-FAK/Paxillin-Akt-GSK3β cascade. Our study establishes a framework for elucidating how glucocorticoid-mediated stress inhibits myogenesis and offers insights for controlling stress-induced muscular dysplasia/atrophy and improving meat production/quality in livestock.