title: Muscle ectopic fat deposition contributes to anabolic resistance in obese sarcopenic old rats through eIF2α activation.
abstract: Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synthesis. Intramuscular ceramide accumulation has been implicated in insulin resistance during obesity. We aimed to measure IS, muscle ceramide level, protein synthesis, and activation of intracellular signaling pathways involved in translation initiation in male Wistar young (YR, 6-month) and old (OR, 25-month) rats receiving a low- (LFD) or a high-fat diet (HFD) for 10 weeks. A corresponding cellular approach using C2C12 myotubes treated with palmitate to induce intracellular ceramide deposition was taken. A decreased ability of adipose tissue to store lipids together with a reduced adipocyte diameter and a development of fibrosis were observed in OR after the HFD. Consequently, OR fed the HFD were insulin resistant, showed a strong increase in intramuscular ceramide level and a decrease in muscle protein synthesis associated with increased eIF2α phosphorylation. The accumulation of intramuscular lipids placed a lipid burden on mitochondria and created a disconnect between metabolic and regulating pathways in skeletal muscles of OR. In C2C12 cells, palmitate-induced ceramide accumulation was associated with a decreased protein synthesis together with upregulated eIF2α phosphorylation. In conclusion, a reduced ability to expand adipose tissues was found in OR, reflecting a lower lipid buffering capacity. Muscle mitochondrial activity was affected in OR conferring a reduced ability to oxidize fatty acids entering the muscle cell. Hence, OR were more prone to ectopic muscle lipid accumulation than YR, leading to decreased muscle protein anabolism. This metabolic change is a potential therapeutic target to counter sarcopenic obesity.
authors.affiliation: Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, Clermont-Ferrand, F-63000, France; INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63000, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tardif
authors.forename: Jérôme
authors.initials: J
authors.lastname: Salles
authors.forename: Christelle
authors.initials: C
authors.lastname: Guillet
authors.forename: Joan
authors.initials: J
authors.lastname: Tordjman
authors.forename: Sophie
authors.initials: S
authors.lastname: Reggio
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Landrier
authors.forename: Christophe
authors.initials: C
authors.lastname: Giraudet
authors.forename: Véronique
authors.initials: V
authors.lastname: Patrac
authors.forename: Justine
authors.initials: J
authors.lastname: Bertrand-Michel
authors.forename: Carole
authors.initials: C
authors.lastname: Migne
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Collin
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chardigny
authors.forename: Yves
authors.initials: Y
authors.lastname: Boirie
authors.forename: Stéphane
authors.initials: S
authors.lastname: Walrand
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000375:Aging / Q000378:metabolism; D000818:Animals; D002518:Ceramides; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D055948:Sarcopenia / Q000378:metabolism*; D015398:Signal Transduction; D019892:eIF-2 Kinase
chemical_list: D002518:Ceramides; D015852:Eukaryotic Initiation Factor-2; D019892:eIF-2 Kinase
keywords: ceramide; eIF2α signaling; high-fat diet; muscle protein synthesis; obesity; sarcopenia