Glucosamine induces increased musclin gene expression through endoplasmic reticulum stress-induced unfolding protein response signaling pathways in mouse skeletal muscle cells

Food Chem Toxicol. 2019 Mar;125:95-105. doi: 10.1016/j.fct.2018.12.051. Epub 2018 Dec 30.

Abstract

Glucosamine (GlcN) is a dietary supplement that is widely used to promote joint health. Reports have demonstrated that oral GlcN adversely affects glucose metabolism. Here, we found that oral administration of GlcN induced insulin resistance (IR) and increased plasma glucose levels in mice. Musclin is a muscle-secreted cytokine that participates in the development and aggravation of diabetes. In this study, we found that increased expression of the musclin plays a pathogenic role in GlcN-induced IR in mice. Additional in vivo and in vitro studies showed that 4-PBA inhibited GlcN-induced endoplasmic reticulum (ER) stress and reduced musclin expression, indicating that ER stress might be closely linked to musclin expression. Moreover, the inhibition of musclin gene expression was also observed when sh-RNAs and small molecular compound inhibitors inhibited ER stress-induced PERK and IRE1-associated unfolding protein response (UPR) signaling pathways, and the CRISPR/Cas9 genome editing technology knockout the ATF6-associated UPR pathway in C2C12 myotubes cells. Silencing of the expression of musclin effectively relieved GlcN-affected phosphorylation of Akt, glucose intake and glycogen synthesis. These results suggest that GlcN increased musclin gene expression though UPR, and musclin represents an important mechanism underlying GlcN-induced IR in mice.

Keywords: Glucosamine; Insulin resistance; Musclin; Skeletal muscle cells; Unfolding protein response.

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Line
  • Endoplasmic Reticulum Stress / drug effects*
  • Gene Expression Regulation / drug effects*
  • Glucosamine / administration & dosage
  • Glucosamine / pharmacology*
  • Insulin Resistance
  • Mice
  • Muscle Proteins / genetics*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Signal Transduction / drug effects*
  • Transcription Factors / genetics*
  • Unfolded Protein Response*

Substances

  • Muscle Proteins
  • Ostn protein, mouse
  • Transcription Factors
  • Glucosamine