Sirt3 Regulates Metabolic Flexibility of Skeletal Muscle Through Reversible Enzymatic Deacetylation

被引:216
作者
Jing, Enxuan [1 ]
O'Neill, Brian T. [1 ]
Rardin, Matthew J. [2 ]
Kleinridders, Andre [1 ]
Ilkeyeva, Olga R. [3 ]
Ussar, Siegfried [1 ]
Bain, James R. [3 ]
Lee, Kevin Y. [1 ]
Verdin, Eric M. [4 ,5 ]
Newgard, Christopher B. [3 ]
Gibson, Bradford W. [2 ]
Kahn, C. Ronald [1 ]
机构
[1] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA
[2] Buck Inst Res Aging, Novato, CA USA
[3] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[4] Gladstone Inst Virol & Immunol, San Francisco, CA USA
[5] Univ Calif San Francisco, Dept Med, San Francisco, CA USA
基金
美国国家卫生研究院;
关键词
PYRUVATE-DEHYDROGENASE COMPLEX; LYSINE ACETYLATION; INSULIN-RESISTANCE; CONTRACTILE ACTIVITY; PROTEIN ACETYLATION; GLUCOSE-TRANSPORT; BETA-CELLS; MITOCHONDRIAL; PHOSPHORYLATION; DEFICIENCY;
D O I
10.2337/db12-1650
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Sirt3 is an NAD(+)-dependent deacetylase that regulates mitochondrial function by targeting metabolic enzymes and proteins. In fasting mice, Sirt3 expression is decreased in skeletal muscle resulting in increased mitochondrial protein acetylation. Deletion of Sirt3 led to impaired glucose oxidation in muscle, which was associated with decreased pyruvate dehydrogenase (PDH) activity, accumulation of pyruvate and lactate metabolites, and an inability of insulin to suppress fatty acid oxidation. Antibody-based acetyl-peptide enrichment and mass spectrometry of mitochondrial lysates from WT and Sirt3 KO skeletal muscle revealed that a major target of Sirt3 deacetylation is the E1 subunit of PDH (PDH E1). Sirt3 knockout in vivo and Sirt3 knockdown in myoblasts in vitro induced hyperacetylation of the PDH E1 subunit, altering its phosphorylation leading to suppressed PDH enzymatic activity. The inhibition of PDH activity resulting from reduced levels of Sirt3 induces a switch of skeletal muscle substrate utilization from carbohydrate oxidation toward lactate production and fatty acid utilization even in the fed state, contributing to a loss of metabolic flexibility. Thus, Sirt3 plays an important role in skeletal muscle mitochondrial substrate choice and metabolic flexibility in part by regulating PDH function through deacetylation.
引用
收藏
页码:3404 / 3417
页数:14
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