|Mezei, Orsolya - BAYLOR COLLEGE MED|
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: July 8, 2006
Publication Date: October 4, 2006
Citation: Mezei, O., Tong, Q. 2006. A mitochondrial sirtuin, SIRT3, regulates muscle differentiation and metabolism [abstract]. In: Cold Spring Harbor Symposium: Molecular Genetics of Aging, October 4-6, 2006, Cold Spring Harbor, New York. p. 222. Technical Abstract: SIRT3 is a member of the sirtuin family of NAD-dependent deacetylases and is localized to the mitochondria. SIRT3 is highly expressed in brown adipose tissue, heart, muscle, and metabolically active tissue enriched with mitochondria. Recent reports found that SIRT3 is able to deacetylate and regulate the function of acyl CoA synthetase 2, the mitochondrial enzyme responsible for converting acetate into acetyl CoA. We previously demonstrated that in mice, cold exposure or caloric restriction leads to increased SIRT3 gene expression in brown adipose, resulting in induced PGC-1alpha and UCP-1 expression and increased oxygen consumption. We report here that murine SIRT3 is expressed higher in the slow oxidative type I soleus muscle as compared to the fast type II extensor digitorum longus muscle and gastrocnemius muscle. The protein level of SIRT3 in mouse hindlimb muscles is down regulated in response to three months of high fat diet feeding. Forced expression of SIRT3 in the C2C12 myoblasts elevates PGC-1alpha and UCP3 gene expression and decreases cellular hydrogen peroxide levels. Furthermore, the expression of SIRT3 increases cellular glucose uptake and beta-oxidation, whereas knockdown of SIRT3 expression results in excess triglyceride accumulation. Finally, forced SIRT3 expression inhibits myocyte differentiation as characterized by decreased expression of MyoD and other myocyte markers. SIRT3 enzymatic activity is required for this action, whereas a SIRT3 deacetylase mutant actually promotes myocytes differentiation. Our results suggest that SIRT3 regulates muscle differentiation and metabolic function.