The unfolded protein response is activated in skeletal muscle by high-fat feeding: potential role in the downregulation of protein synthesis

Louise Deldicque, Patrice D. Cani, Andrew Philp, Jean-Marc Raymackers, Paul J. Meakin, Michael L. J. Ashford, Nathalie M. Delzenne, Marc Francaux, Keith Baar

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    Deldicque L, Cani PD, Philp A, Raymackers JM, Meakin PJ, Ashford ML, Delzenne NM, Francaux M, Baar K. The unfolded protein response is activated in skeletal muscle by high-fat feeding: potential role in the downregulation of protein synthesis. Am J Physiol Endocrinol Metab 299: E695-E705, 2010. First published May 25, 2010; doi: 10.1152/ajpendo.00038.2010.-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, IRE1 alpha, 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, IRE1 alpha, 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 C2C12 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.

    Original languageEnglish
    Pages (from-to)E695-E705
    Number of pages11
    JournalAmerican Journal of Physiology, Endocrinology and Metabolism
    Issue number5
    Publication statusPublished - Nov 2010


    • endoplasmic reticulum stress
    • binding protein
    • X box binding protein-1
    • ribosomal protein S6 kinase
    • protein synthesis

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