Sir2 Regulates Skeletal Muscle Differentiation as a Potential Sensor of the Redox State

• Autores: Marcella Fulco, Simona Iezzi, R. Louis Schiltz
• Localización: Molecular cell, ISSN 1097-2765, Vol. 12, Nº 1, 2003, pág. 51
• Idioma: inglés
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• Resumen

  • 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.