Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state.
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.
Fulco
Marcella
M
Muscle Gene Expression Group, Laboratory of Muscle Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Schiltz
R Louis
RL
Iezzi
Simona
S
King
M Todd
MT
Zhao
Po
P
Kashiwaya
Yoshihiro
Y
Hoffman
Eric
E
Veech
Richard L
RL
Sartorelli
Vittorio
V
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D051548:Histone Acetyltransferases; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000196:embryology* / Q000201:enzymology*; D017570:MyoD Protein / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D056565:Sirtuin 2; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
D017570:MyoD Protein; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D009243:NAD; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D037761:Sirtuins