Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production

被引:382
作者
Jing, Enxuan [1 ]
Emanuelli, Brice [1 ]
Hirschey, Matthew D. [2 ,3 ]
Boucher, Jeremie [1 ]
Lee, Kevin Y. [1 ]
Lombard, David [4 ]
Verdin, Eric M. [2 ,3 ]
Kahn, C. Ronald [1 ]
机构
[1] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA
[2] Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA
[3] Univ Calif San Francisco, San Francisco, CA 94143 USA
[4] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA
关键词
mitochondrial metabolism; protein acetylation; DIABETES-MELLITUS; GENE-EXPRESSION; POTENTIAL ROLE; RESISTANCE; STRESS; HOMOLOG; FAT; PHOSPHORYLATION; RESPIRATION; DEACETYLASE;
D O I
10.1073/pnas.1111308108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Sirt3 is a member of the sirtuin family of protein deacetylases that is localized in mitochondria and regulates mitochondrial function. Sirt3 expression in skeletal muscle is decreased in models of type 1 and type 2 diabetes and regulated by feeding, fasting, and caloric restriction. Sirt3 knockout mice exhibit decreased oxygen consumption and develop oxidative stress in skeletal muscle, leading to JNK activation and impaired insulin signaling. This effect is mimicked by knockdown of Sirt3 in cultured myoblasts, which exhibit reduced mitochondrial oxidation, increased reactive oxygen species, activation of JNK, increased serine and decreased tyrosine phosphorylation of IRS-1, and decreased insulin signaling. Thus, Sirt3 plays an important role in diabetes through regulation of mitochondrial oxidation, reactive oxygen species production, and insulin resistance in skeletal muscle.
引用
收藏
页码:14608 / 14613
页数:6
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