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

By Nathan L. Price, A. P. Gomes, A. Ling, F. V. Duarte, A. Martín-Montalvo, Brian J. North, B. Agarwal, Lan Ye, G. Ramadori, J. Teodoro and 12 more. Cell Metabolism, 2012

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SUMMARY 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 germ-line SIRT1 knockouts, we have developed the first 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.

Subfields: Epidemiology, Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/a72e2faabefa57f30f32e4ba4b4c120ce2e95c8b

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Citations in the corpus

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism (2020, background): “Indeed, treatment with resveratrol of SIRT1 KO mice does not show beneficial properties [230].”
The hallmarks of aging. (2013, background): “Moreover, SIRT1 and AMPK can engage in a positive feedback loop, thus connecting both sensors of low-energy states into a unified response (Price et al., 2012).”
Mitochondrial Dysfunction in Neurodegenerative Diseases (2012, background): “…in a study by Sinclair's group, which used a conditional SIRT1 knockout mouse to show that with moderate doses of resveratrol in vitro or in vivo the increases in phosphorylated AMPK, NAD ϩ , liver kinase B1 acetylation, and mitochondrial function entirely depended on SIRT1 (Price et al., 2012).”
Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (2013, methodology): “Some of the health benefits of SIRT1 have also been linked to improvedmitochondrial function (Baur et al., 2006; Gerhart-Hines et al., 2007; Price et al., 2012; Rodgers et al., 2005).”
The Mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance (2015, positive): “Again, we used 448 Cell Metabolism 21, 443–454, March 3, 2015 ª2015 Elsevier Inc. siRNA to knock down SIRT1 (Figure S3J) as well as the SIRT1 inhibitor EX527 (Price et al., 2012) in MOTS-c-ST cells.”
Sirt1 and the Mitochondria (2016, background): “Class I HDACs (HDACs 1, 2, 3 and 8) are homologous with the yeast Reduced Potassium Deficiency 3 (RPD3), are ubiquitously expressed, and are primarily localized to the nucleus.”