Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt

Dev Cell. 2008 May;14(5):661-73. doi: 10.1016/j.devcel.2008.02.004.

Abstract

It is intuitive to speculate that nutrient availability may influence differentiation of mammalian cells. Nonetheless, a comprehensive complement of the molecular determinants involved in this process has not been elucidated yet. Here, we have investigated how nutrients (glucose) affect skeletal myogenesis. Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt. Indeed, GR augmented the Nampt activity, which consequently modified the intracellular [NAD+]:[NADH] ratio and nicotinamide levels, and mediated inhibition of skeletal myogenesis. Skeletal myoblasts derived from SIRT1+/- heterozygous mice were resistant to the effects of either GR or AMPK activation. These experiments reveal that AMPK, Nampt, and SIRT1 are the molecular components of a functional signaling pathway that allows skeletal muscle cells to sense and react to nutrient availability.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Cell Differentiation*
  • Cell Line
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Enzyme Activation
  • Food Deprivation
  • Gene Expression Regulation
  • Glucose / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Multienzyme Complexes / metabolism*
  • Myoblasts, Skeletal / cytology*
  • Myoblasts, Skeletal / enzymology*
  • NAD / metabolism
  • Nicotinamide Phosphoribosyltransferase / genetics
  • Nicotinamide Phosphoribosyltransferase / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sirtuin 1
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Transcription, Genetic

Substances

  • Cytokines
  • Multienzyme Complexes
  • NAD
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Sirtuins
  • Glucose