TY - JOUR
T1 - Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge
AU - Nohara, Kazunari
AU - Mallampalli, Venkata
AU - Nemkov, Travis
AU - Wirianto, Marvin
AU - Yang, Jiah
AU - Ye, Youqiong
AU - Sun, Yuxiang
AU - Han, Leng
AU - Esser, Karyn A.
AU - Mileykovskaya, Eugenia
AU - D’Alessandro, Angelo
AU - Green, Carla B.
AU - Takahashi, Joseph S.
AU - Dowhan, William
AU - Yoo, Seung Hee
AU - Chen, Zheng
N1 - Funding Information:
We thank K. Mawatari, Y. Kim, and S. Yan for technical assistance, S.H. Baek for reagents, M. Lee for help with statistical analysis, C.C. Lee and Z. Zhao for help with metabolic chamber, and R. Berdeaux for help with treadmill assays. This work is in part supported by The Welch Foundation (AU-1731-20160319) and NIH/NIA (R01AG045828, R01AG061901) to Z.C., The Welch Foundation (AU-1971-20180324), and NIH/NIGMS (R01GM114424) to S.-H.Y., R01GM115969 and John S. Dunn Research Foundation Grant to W.D., NIH/NIA (R01AG045795) to J.S.T., Cancer Prevention & Research Institute of Texas (RR150085) to L.H., and NIH T32 HL007171 to T. N. J.S.T. is an Investigator in the Howard Hughes Medical Institute.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-11926-y
DO - 10.1038/s41467-019-11926-y
M3 - Article
C2 - 31462679
AN - SCOPUS:85071606278
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3923
ER -