SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function

Abstract

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.

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…Several authors have shown deficits in mitochondrial function in the spinal cord and muscles of both human patients [64] and animal models of ALS [65][66][67]. Resveratrol improves mitochondrial function and induces biogenesis, although there is some controversy about whether this effect is mediated by AMPK activation [18] or by Sirt1 [16,68]. Since both Sirt1 and AMPK were found over-activated in SOD1 G93A animals treated with resveratrol, we performed a detailed analysis on mitochondria.…”

“…Sirt1 is a NAD + -dependent deacetylase that plays an important role regulating cell metabolism and has recently been postulated as a neuroprotective element in several neurodegenerative disorders [13]. Sirt1 induces protective effects since it is upstream of multiple effectors that participate in several cell processes, such as inflammation [43], autophagy [45] and mitochondrial function [16,46], all of them related to ALS physiopathology [5,56]. In the present work, we found that Sirt1 was overexpressed in spinal MNs of SOD1 G93A mice after resveratrol administration.…”

“…Recent evidence has demonstrated that resveratrol promotes mitochondrial biogenesis through the activation of AMPK [16]. Thus, we first assessed the expression and activation of AMPK by analyzing the active phospho-AMPK and total AMPK forms.…”

“…Its activation has been shown to protect against neurodegeneration in several neurodegenerative disorders [13]. In fact, Sirt1 may promote neuroprotection by the modulation of several cellular pathways, such as autophagy [14,15] and mitochondrial biogenesis [16]. On the other hand, it is also accepted that resveratrol benefits may be mediated through AMPK activation [16,17].…”

“…In fact, Sirt1 may promote neuroprotection by the modulation of several cellular pathways, such as autophagy [14,15] and mitochondrial biogenesis [16]. On the other hand, it is also accepted that resveratrol benefits may be mediated through AMPK activation [16,17]. It has been proposed that resveratrol works primarily by activating AMPK, which then activates Sirt1 indirectly by elevating intracellular levels of its cosubstrate NAD+ [18,19].…”