title: The unfolded protein response is activated in skeletal muscle by high-fat feeding: potential role in the downregulation of protein synthesis.
abstract: High-fat diets are known to decrease muscle protein synthesis, the adaptation to overload, and insulin sensitivity. Conditions that disrupt endoplasmic reticulum (ER) homeostasis lead to the activation of the unfolded protein response (UPR) that is associated with decreases in protein synthesis, chronic inflammation, and insulin resistance. The purpose of the present study was to establish whether ER stress is induced by a high-fat diet in skeletal muscle and whether ER stress can decrease mTORC1 activity and protein synthesis in muscle cells. Two independent protocols of high-fat feeding activated the UPR in mice. In the first study, mice consuming a high-fat diet containing 70% fat and <1% carbohydrates for 6 wk showed higher markers of the UPR (BiP, IRE1α, and MBTPS2) in the soleus and in the tibialis anterior muscles and ATF4 in the tibialis anterior (P < 0.05). In the second study, a 20-wk high-fat diet containing 46% fat and 36% carbohydrates also increased BiP, IRE1α, and phospho-PERK protein and the expression of ATF4, CHOP, and both the spliced and unspliced forms of XBP1 in the plantar flexors (P < 0.05). In C(2)C(12) muscle cells, tunicamycin, thapsigargin, and palmitic acid all increased UPR markers and decreased phosphorylation of S6K1 (P < 0.05). Collectively, these data show that a high-fat diet activates the UPR in mouse skeletal muscle in vivo. In addition, in vitro studies indicate that palmitic acid, and other well-known ER stress inducers, triggered the UPR in myogenic cells and led to a decrease in protein synthesis and mTORC1 activity.
authors.affiliation: Institute of Neurosciences, UCLouvain, Louvain-la-Neuve, Belgium.
authors.forename: Louise
authors.initials: L
authors.lastname: Deldicque
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Andrew
authors.initials: A
authors.lastname: Philp
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Raymackers
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Meakin
authors.forename: Michael L J
authors.initials: ML
authors.lastname: Ashford
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Delzenne
authors.forename: Marc
authors.initials: M
authors.lastname: Francaux
authors.forename: Keith
authors.initials: K
authors.lastname: Baar
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage* / Q000378:metabolism; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D004722:Endoribonucleases; D009124:Muscle Proteins; D009842:Oligopeptides; D017346:Protein Serine-Threonine Kinases; D012313:RNA; D000071701:Regulatory Factor X Transcription Factors; D012697:Serine Endopeptidases; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C081452:Atf4 protein, mouse; C539791:Bax-inhibiting peptide, BIP; C519509:Crtc1 protein, mouse; C497250:Ddit3 protein, mouse; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse