The unfolded protein response in human skeletal muscle is not involved in the onset of glucose tolerance impairment induced by a fat-rich diet

Eur J Appl Physiol. 2011 Jul;111(7):1553-8. doi: 10.1007/s00421-010-1783-1. Epub 2010 Dec 25.


Endoplasmic reticulum (ER) stress in pancreas, liver, and adipose tissue is a key event in the pathogenesis of obesity-related metabolic disease. Lipid-induced ER stress in liver and adipose tissue leads to inhibition of insulin signaling. Whether this mechanism exists in skeletal muscle is currently unknown. The present study aimed at assessing the ER stress response in skeletal muscle of subjects receiving a hyper-caloric fat-rich diet (HFD). Seven healthy males (20.6 ± 0.5 years; 70.9 ± 3.4 kg) volunteered to participate in the study. They received a hyper-caloric (+30% kcal) fat-rich (50% kcal) diet for 6 weeks. An oral glucose tolerance test (OGTT) was performed, and muscle biopsies were taken before and after HFD. HFD increased body mass by ~3 kg (P = 0.007) and the sum of skinfolds by 15% (P = 0.003). After HFD, blood glucose concentrations were higher during OGTT (two-way ANOVA, P = 0.023; +45% at 20 min, P = 0.002), and fasting plasma insulin level tended to be higher (+20%). HFD increased intramyocellular lipids content by ~50 and 75% in type I (P = 0.0009) and IIa fibers (P = 0.002), respectively. The protein expression of inositol-requiring enzyme 1α, protein kinase R-like ER protein kinase, BiP and calnexin and the mRNA level of spliced X box binding protein-1, CCAAT/enhancer binding protein homologous protein and activating transcription factor 4 were not changed after HFD. Despite the increase in body mass, subcutaneous fat deposits, and intramyocellular lipids content, ER stress markers were unchanged in skeletal muscle of subjects receiving a HFD for 6 weeks. This suggests that the onset of glucose intolerance is not related to ER stress in skeletal muscle.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / anatomy & histology
  • Adult
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diet, Atherogenic*
  • Dietary Fats / adverse effects
  • Dietary Fats / pharmacology*
  • Glucose Intolerance / etiology*
  • Glucose Intolerance / metabolism
  • Humans
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / physiology
  • Lipids / blood
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / physiology
  • Unfolded Protein Response / drug effects
  • Unfolded Protein Response / physiology*
  • Weight Gain / drug effects
  • Weight Gain / physiology
  • Young Adult


  • Blood Glucose
  • Dietary Fats
  • Lipids