title: Fructose-derived advanced glycation end-products drive lipogenesis and skeletal muscle reprogramming via SREBP-1c dysregulation in mice.
abstract: Advanced Glycation End-Products (AGEs) have been recently related to the onset of metabolic diseases and related complications. Moreover, recent findings indicate that AGEs can endogenously be formed by high dietary sugars, in particular by fructose which is widely used as added sweetener in foods and drinks. The aim of the present study was to investigate the impact of a high-fructose diet and the causal role of fructose-derived AGEs in mice skeletal muscle morphology and metabolism. C57Bl/6J mice were fed a standard diet (SD) or a 60% fructose diet (HFRT) for 12 weeks. Two subgroups of SD and HFRT mice received the anti-glycative compound pyridoxamine (150 mg/kg/day) in the drinking water. At the end of protocol high levels of AGEs were detected in both plasma and gastrocnemius muscle of HFRT mice associated to impaired expression of AGE-detoxifying AGE-receptor 1. In gastrocnemius, AGEs upregulated the lipogenesis by multiple interference on SREBP-1c through downregulation of the SREBP-inhibiting enzyme SIRT-1 and increased glycation of the SREBP-activating protein SCAP. The AGEs-induced SREBP-1c activation affected the expression of myogenic regulatory factors leading to alterations in fiber type composition, associated with reduced mitochondrial efficiency and muscular strength. Interestingly, pyridoxamine inhibited AGEs generation, thus counteracting all the fructose-induced alterations. The unsuspected involvement of diet-derived AGEs in muscle metabolic derangements and proteins reprogramming opens new perspectives in pathogenic mechanisms of metabolic diseases.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Italy. Electronic address: raffaella.mastrocola@unito.it.
authors.forename: R
authors.initials: R
authors.lastname: Mastrocola
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Nigro
authors.affiliation: Department of Drug Science and Technology, University of Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Medana
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Dal Bello
authors.affiliation: Department of Medical Sciences, University of Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Boccuzzi
authors.affiliation: Department of Drug Science and Technology, University of Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Collino
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Aragno
mesh_terms: D050156:Adipogenesis; D000818:Animals; D065150:Cellular Reprogramming; D004032:Diet; D005632:Fructose / Q000009:adverse effects*; D017127:Glycation End Products, Advanced / Q000097:blood*; D050155:Lipogenesis; D008297:Male; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology*
chemical_list: D017127:Glycation End Products, Advanced; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D005632:Fructose
keywords: AGEs; Carboxy methyllysine; Fructose; Lipogenesis; Mitochondrial oxidation; Muscle strength; Myogenic regulatory factors; Pyridoxamine; SREBP-1c