Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge

被引：138

作者：

Nohara, Kazunari ^{[1
]}

Mallampalli, Venkata ^{[1
]}

Nemkov, Travis ^{[2
]}

Wirianto, Marvin ^{[1
]}

Yang, Jiah ^{[1
]}

Ye, Youqiong ^{[1
]}

Sun, Yuxiang ^{[3
]}

Han, Leng ^{[1
]}

Esser, Karyn A. ^{[4
]}

Mileykovskaya, Eugenia ^{[1
]}

D'Alessandro, Angelo ^{[2
]}

Green, Carla B. ^{[5
]}

Takahashi, Joseph S. ^{[5
,6
]}

Dowhan, William ^{[1
]}

Yoo, Seung-Hee ^{[1
]}

Chen, Zheng ^{[1
]}

机构：

[1] Univ Texas Hlth Sci Ctr Houston, Dept Biochem & Mol Biol, 6431 Fannin St, Houston, TX 77030 USA

[2] Univ Colorado Denver Anschutz Med Campus, Dept Biochem & Mol Genet, Aurora, CO 80045 USA

[3] Texas A&M Univ, Dept Nutr & Food Sci, College Stn, TX 77843 USA

[4] Univ Florida, Coll Med, Dept Physiol & Funct Genom, Gainesville, FL 32610 USA

[5] Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

[6] Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

PERIPHERAL CIRCADIAN CLOCKS; LIFE-SPAN; TRANSCRIPTIONAL ARCHITECTURE; REV-ERB; ORGANIZATION; RESTRICTION; RHYTHMS; MICE; SUPERCOMPLEXES; COMPLEXES;

D O I：

10.1038/s41467-019-11926-y

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：

Circadian disruption aggravates age-related decline and mortality. However, it remains unclear whether circadian enhancement can retard aging in mammals. We previously reported that the small molecule Nobiletin (NOB) activates ROR (retinoid acid receptor-related orphan receptor) nuclear receptors to potentiate circadian oscillation and protect against metabolic dysfunctions. Here we show that NOB significantly improves metabolic fitness in naturally aged mice fed with a regular diet (RD). Furthermore, NOB enhances healthy aging in mice fed with a high-fat diet (HF). In HF skeletal muscle, the NOB-ROR axis broadly activates genes for mitochondrial respiratory chain complexes (MRCs) and fortifies MRC activity and architecture, including Complex II activation and supercomplex formation. These mechanisms coordinately lead to a dichotomous mitochondrial optimization, namely increased ATP production and reduced ROS levels. Together, our study illustrates a focal mechanism by a clock-targeting pharmacological agent to optimize skeletal muscle mitochondrial respiration and promote healthy aging in metabolically stressed mammals.

引用

页数：15

共 70 条

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