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

Kazunari Nohara, Venkata Mallampalli, Travis Nemkov, Marvin Wirianto, Jiah Yang, Youqiong Ye, Yuxiang Sun, Leng Han, Karyn A. Esser, Eugenia Mileykovskaya, Angelo D’Alessandro, Carla B. Green, Joseph S. Takahashi, William Dowhan, Seung-Hee Yoo and Zheng Chen ()
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Kazunari Nohara: The University of Texas Health Science Center at Houston
Venkata Mallampalli: The University of Texas Health Science Center at Houston
Travis Nemkov: University of Colorado Denver - Anschutz Medical Campus
Marvin Wirianto: The University of Texas Health Science Center at Houston
Jiah Yang: The University of Texas Health Science Center at Houston
Youqiong Ye: The University of Texas Health Science Center at Houston
Yuxiang Sun: Texas A&M University
Leng Han: The University of Texas Health Science Center at Houston
Karyn A. Esser: University of Florida College of Medicine
Eugenia Mileykovskaya: The University of Texas Health Science Center at Houston
Angelo D’Alessandro: University of Colorado Denver - Anschutz Medical Campus
Carla B. Green: The University of Texas Southwestern Medical Center
Joseph S. Takahashi: The University of Texas Southwestern Medical Center
William Dowhan: The University of Texas Health Science Center at Houston
Seung-Hee Yoo: The University of Texas Health Science Center at Houston
Zheng Chen: The University of Texas Health Science Center at Houston

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11926-y

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