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
  • 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. [email protected].
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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