2. Academic Validation
  3. Nobiletin fortifies mitochondrial respiration in skeletal muscle to promote healthy aging against metabolic challenge

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

  • Nat Commun. 2019 Aug 28;10(1):3923. doi: 10.1038/s41467-019-11926-y.
Kazunari Nohara 1,  Venkata Mallampalli 1,  Travis Nemkov 2,  Marvin Wirianto 1,  Jiah Yang 1,  Youqiong Ye 1,  Yuxiang Sun 3,  Leng Han 1,  Karyn A Esser 4,  Eugenia Mileykovskaya 1,  Angelo D'Alessandro 2,  Carla B Green 5,  Joseph S Takahashi 5 6,  William Dowhan 1,  Seung-Hee Yoo 1,  Zheng Chen 7
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, Texas, 77030, USA.
  • 2 Department of Biochemistry and Molecular Genetics, University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, 80045, USA.
  • 3 Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, 77843, USA.
  • 4 Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, 32610-0274, USA.
  • 5 Department of Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas, 75390, USA.
  • 6 Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA.
  • 7 Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, Texas, 77030, USA. Zheng.chen.1@uth.tmc.edu.
PMID: 31462679 DOI: 10.1038/s41467-019-11926-y
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.

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