SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function

Nathan L. Price, Ana P. Gomes, Alvin J.Y. Ling, Filipe V. Duarte, Alejandro Martin-Montalvo, Brian J. North, Beamon Agarwal, Lan Ye, Giorgio Ramadori, Joao S. Teodoro, Basil P. Hubbard, Ana T. Varela, James G. Davis, Behzad Varamini, Angela Hafner, Ruin Moaddel, Anabela P. Rolo, Roberto Coppari, Carlos M. Palmeira, Rafael De CaboJoseph A. Baur, David A. Sinclair

Research output: Contribution to journalArticlepeer-review

906 Scopus citations

Abstract

Resveratrol induces mitochondrial biogenesis and protects against metabolic decline, but whether SIRT1 mediates these benefits is the subject of debate. To circumvent the developmental defects of germline SIRT1 knockouts, we have developed an inducible system that permits whole-body deletion of SIRT1 in adult mice. Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased NAD + levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. A mouse overexpressing SIRT1 mimicked these effects. A high dose of resveratrol activated AMPK in a SIRT1-independent manner, demonstrating that resveratrol dosage is a critical factor. Importantly, at both doses of resveratrol no improvements in mitochondrial function were observed in animals lacking SIRT1. Together these data indicate that SIRT1 plays an essential role in the ability of moderate doses of resveratrol to stimulate AMPK and improve mitochondrial function both in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)675-690
Number of pages16
JournalCell Metabolism
Volume15
Issue number5
DOIs
StatePublished - May 2 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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