Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling

In this study, we investigated whether AGEs could exacerbate skeletal muscle atrophy and its related insulin resistance. Mice were exposed to AGEs. Forkhead box O1 (FOXO1) was silenced by a constructed viral vector carrying siRNA. Skeletal muscle atrophy was evaluated by H&E, oil red O, myosin skeletal heavy chain (MHC) and laminin immunofluorescent stains. Reactive oxygen species (ROS) generation was assessed by DHE stain. Western blotting was used to evaluate protein expression and phosphorylation. Insulin resistance was monitored by insulin tolerance test (ITT) and glucose infusion rate (GIR). Mice exposed to AGEs showed insulin resistance which was evidenced by reduced ITT and GIR. H&E and MHC immunofluorescent stains suggested reduced cross-sectional muscle fiber area. Laminin immunofluorescent and Oil red O stains indicated increased intramuscular fibrosis and lipid deposit respectively. AGEs exposure induced ROS generation, increased phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and FOXO1, facilitated FOXO1 nuclear translocation and elevated expression of muscle atrophy F-box (MAFbx) in gastrocnemius muscle. foxo1 silencing significantly suppressed skeletal muscle atrophy and insulin resistance without affecting ROS production. AGEs exacerbated skeletal muscle atrophy and insulin resistance by activating PERK/FOXO1 signaling pathway in skeletal muscle.PMID:36724125 | DOI:10.1152/ajpendo.00218.2022
Source: American Journal of Physiology. Endocrinology and Metabolism - Category: Physiology Authors: Source Type: research