PMID- 36724125 OWN - NLM STAT- MEDLINE DCOM- 20230314 LR - 20230410 IS - 1522-1555 (Electronic) IS - 0193-1849 (Linking) VI - 324 IP - 3 DP - 2023 Mar 1 TI - Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling. PG - E279-E287 LID - 10.1152/ajpendo.00218.2022 [doi] AB - Skeletal muscle atrophy is often found in patients with type 2 diabetes mellitus (T2DM), which is characterized by insulin resistance. As the largest tissue in the body, skeletal muscle plays important roles in insulin resistance. Advanced glycation end products (AGEs) are a type of toxic metabolite that are representative of multiple pathophysiological changes associated with T2DM. Mice were exposed to AGEs. Forkhead box O1 (FOXO1) was silenced by using a constructed viral vector carrying siRNA. Skeletal muscle atrophy was evaluated by using hematoxylin-eosin (H&E), oil red O, myosin skeletal heavy chain (MHC), and laminin immunofluorescent stains. Reactive oxygen species (ROS) generation was assessed by using the dihydroethidium (DHE) stain. Western blotting was used to evaluate protein expression and phosphorylation. Insulin resistance was monitored via the insulin tolerance test and the glucose infusion rate (GIR). Mice exposed to AGEs showed insulin resistance, which was evidenced by reduced insulin tolerance 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 deposits, respectively. Exposure to AGEs 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 the PERK/FOXO1 signaling pathway in skeletal muscle.NEW & NOTEWORTHY In this study, we proposed a molecular mechanism underlying the skeletal muscle atrophy-associated insulin resistance in type 2 diabetes mellitus (T2DM). Our investigation suggests that exposure to AGEs, which are characteristic metabolites of T2DM pathology, induces the activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, leading to the upregulation of the protein kinase RNA-like ER kinase (PERK)/forkhead box O1 (FOXO1)/muscle atrophy F-box pathway and subsequent skeletal muscle atrophy, ultimately resulting in insulin resistance. FAU - Du, Haixia AU - Du H AD - Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Department 403, PLA Rocket Force University of Engineering, Xi'an, People's Republic of China. FAU - Ma, Yanpeng AU - Ma Y AD - Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China. FAU - Wang, Xiqiang AU - Wang X AD - Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China. FAU - Zhang, Yong AU - Zhang Y AD - Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China. FAU - Zhu, Ling AU - Zhu L AD - Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China. FAU - Shi, Shuang AU - Shi S AD - Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China. FAU - Pan, Shuo AU - Pan S AUID- ORCID: 0000-0001-7934-572X AD - Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China. FAU - Liu, Zhongwei AU - Liu Z AUID- ORCID: 0000-0002-5548-5450 AD - Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Metabolic and Cardiovascular Diseases Laboratories, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China. AD - Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230201 PL - United States TA - Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism JID - 100901226 RN - G7S71FND9B (oil red O) RN - 0 (Reactive Oxygen Species) RN - EC 2.7.- (Protein Kinases) RN - 63231-63-0 (RNA) RN - 0 (Laminin) RN - 0 (Insulin) RN - 0 (Glycation End Products, Advanced) RN - 0 (Forkhead Box Protein O1) RN - 0 (Foxo1 protein, mouse) SB - IM MH - Mice MH - Animals MH - Reactive Oxygen Species/metabolism MH - *Insulin Resistance/genetics MH - Protein Kinases/metabolism MH - *Diabetes Mellitus, Type 2/metabolism MH - RNA/metabolism MH - Laminin/metabolism MH - Cross-Sectional Studies MH - Signal Transduction/physiology MH - Muscle, Skeletal/metabolism MH - Muscular Atrophy/metabolism MH - Insulin/metabolism MH - Glycation End Products, Advanced/metabolism MH - Forkhead Box Protein O1/metabolism OTO - NOTNLM OT - advanced glycation end products OT - atrophy OT - endoplasmic reticulum stress OT - insulin resistance OT - skeletal muscle EDAT- 2023/02/02 06:00 MHDA- 2023/03/15 06:00 CRDT- 2023/02/01 13:13 PHST- 2023/02/02 06:00 [pubmed] PHST- 2023/03/15 06:00 [medline] PHST- 2023/02/01 13:13 [entrez] AID - 10.1152/ajpendo.00218.2022 [doi] PST - ppublish SO - Am J Physiol Endocrinol Metab. 2023 Mar 1;324(3):E279-E287. doi: 10.1152/ajpendo.00218.2022. Epub 2023 Feb 1.