title: Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated, AMPK-down-regulated, Akt pathway.
abstract: Diabetic myopathy, a less studied complication of diabetes, exhibits the clinical observations characterized by a less muscle mass, muscle weakness and a reduced physical functional capacity. Accumulation of advanced glycation end-products (AGEs), known to play a role in diabetic complications, has been identified in ageing human skeletal muscles. However, the role of AGEs in diabetic myopathy remains unclear. Here, we investigated the effects of AGEs on myogenic differentiation and muscle atrophy in vivo and in vitro. We also evaluated the therapeutic potential of alagebrium chloride (Ala-Cl), an inhibitor of AGEs. Muscle fibre atrophy and immunoreactivity for AGEs, Atrogin-1 (a muscle atrophy marker) and phosphorylated AMP-activated protein kinase (AMPK) expressions were markedly increased in human skeletal muscles from patients with diabetes as compared with control subjects. Moreover, in diabetic mice we found increased blood AGEs, less muscle mass, lower muscular endurance, atrophic muscle size and poor regenerative capacity, and increased levels of muscle AGE and receptor for AGE (RAGE), Atrogin-1 and phosphorylated AMPK, which could be significantly ameliorated by Ala-Cl. Furthermore, in vitro, AGEs (in a dose-dependent manner) reduced myotube diameters (myotube atrophy) and induced Atrogin-1 protein expression in myotubes differentiated from both mouse myoblasts and primary human skeletal muscle-derived progenitor cells. AGEs exerted a negative regulation of myogenesis of mouse and human myoblasts. Ala-Cl significantly inhibited the effects of AGEs on myotube atrophy and myogenesis. We further demonstrated that AGEs induced muscle atrophy/myogenesis impairment via a RAGE-mediated AMPK-down-regulation of the Akt signalling pathway. Our findings support that AGEs play an important role in diabetic myopathy, and that an inhibitor of AGEs may offer a therapeutic strategy for managing the dysfunction of muscle due to diabetes or ageing.
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chen-Yuan
authors.initials: CY
authors.lastname: Chiu
authors.affiliation: Department of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Rong-Sen
authors.initials: RS
authors.lastname: Yang
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Meei-Ling
authors.initials: ML
authors.lastname: Sheu
authors.affiliation: Department of Geriatrics and Gerontology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ding-Cheng
authors.initials: DC
authors.lastname: Chan
authors.affiliation: Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ting-Hua
authors.initials: TH
authors.lastname: Yang
authors.affiliation: Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Keh-Sung
authors.initials: KS
authors.lastname: Tsai
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Departments of Integrated Diagnostics and Therapeutics and Internal Medicine, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Kang
authors.initials: CK
authors.lastname: Chiang
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Paediatrics, National Taiwan University Hospital, Taipei, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000368:Aged; D000818:Animals; D001284:Atrophy / Q000209:etiology / Q000473:pathology; D016022:Case-Control Studies; D003920:Diabetes Mellitus / Q000209:etiology*; D003921:Diabetes Mellitus, Experimental / Q000209:etiology; D015536:Down-Regulation; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D018763:Muscle Fatigue / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism; D018908:Muscle Weakness / Q000209:etiology / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology* / Q000502:physiology; D009135:Muscular Diseases / Q000209:etiology* / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products / Q000502:physiology; D012038:Regeneration / Q000502:physiology; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D017127:Glycation End Products, Advanced; D009124:Muscle Proteins; D000067759:Receptor for Advanced Glycation End Products; D013844:Thiazoles; C406794:alagebrium; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D055372:AMP-Activated Protein Kinases
keywords: advanced glycation end-products; alagebrium chloride; diabetic myopathy