Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state

Mol Cell. 2003 Jul;12(1):51-62. doi: 10.1016/s1097-2765(03)00226-0.


Sir2 is a NAD(+)-dependent histone deacetylase that controls gene silencing, cell cycle, DNA damage repair, and life span. Prompted by the observation that the [NAD(+)]/[NADH] ratio is subjected to dynamic fluctuations in skeletal muscle, we have tested whether Sir2 regulates muscle gene expression and differentiation. Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation. Conversely, cells with decreased Sir2 differentiate prematurely. To inhibit myogenesis, Sir2 requires its NAD(+)-dependent deacetylase activity. The [NAD(+)]/[NADH] ratio decreases as muscle cells differentiate, while an increased [NAD(+)]/[NADH] ratio inhibits muscle gene expression. Cells with reduced Sir2 levels are less sensitive to the inhibition imposed by an elevated [NAD(+)]/[NADH] ratio. These results indicate that Sir2 regulates muscle gene expression and differentiation by possibly functioning as a redox sensor. In response to exercise, food intake, and starvation, Sir2 may sense modifications of the redox state and promptly modulate gene expression.

MeSH terms

  • Acetyltransferases / metabolism
  • Animals
  • Cell Differentiation / genetics*
  • Cell Line
  • Gene Expression Regulation, Developmental / genetics*
  • Histone Acetyltransferases
  • Humans
  • Mice
  • Muscle Fibers, Skeletal / enzymology*
  • Muscle, Skeletal / embryology*
  • Muscle, Skeletal / enzymology*
  • MyoD Protein / metabolism
  • NAD / metabolism
  • Oxidation-Reduction
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sirtuin 2
  • Sirtuins / genetics
  • Sirtuins / metabolism*


  • MyoD Protein
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • NAD
  • Acetyltransferases
  • Histone Acetyltransferases
  • SIRT2 protein, human
  • Sirtuin 2
  • Sirtuins