Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1α

Abstract

Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…Several targets of SIRT1 including PGC‐1α and FoxO1/3 have been previously shown to influence mitochondrial biogenesis, antioxidant formation, and inflammation (Brunet, 2004; Lagouge et al, 2006). While we did not observe a statistically significant impact on these pathways in wild‐type mice with aging (data not shown), it is possible that an effect might have been apparent in older animals, as the SOD1 G93A exhibit more severe neuromuscular pathology that is observed during normal aging.…”

“…Several targets of SIRT1 including PGC‐1α and FoxO1/3 have been previously shown to influence mitochondrial biogenesis, antioxidant formation, and inflammation (Brunet, 2004; Lagouge et al, 2006). These findings are interesting because mitochondrial dysfunction and the formation of reactive oxygen species are thought to occur in SOD1 mutation carriers as well as patients with C9ORF72 mutations, mutant TDP43, and FUS during ALS pathogenesis (Lopez‐Gonzalez et al, 2016; Onesto et al, 2016).…”

“…SIRT1 is a nicotinamide adenine dinucleotide (NAD+)‐dependent deacetylase that catalyzes the removal of acetyl groups from lysine residues on histone proteins, resulting in gene silencing (Braunstein, Rose, Holmes, Allis, & Broach, 1993; Imai, Armstrong, Kaeberlein, & Guarente, 2000; Tanny, Dowd, Huang, Hilz, & Moazed, 1999). SIRT1 also deacetylates transcription factors including PGC1α, which induces mitochondrial oxidative phosphorylation (Lagouge et al, 2006), p53, which promotes cell survival (Luo et al, 2001; Vaziri et al, 2001) and triggers adaptation to calorie restriction with its accompanying stress resistance (Guarente, 2013). Through these actions, SIRT1 functions to maintain cellular homeostasis and thereby prevent age‐related pathological changes.…”

“…To date, it has been postulated that oxidative stress, mitochondrial dysfunction, impaired autophagy, and decreased release of trophic factors (Carnio et al, 2014; Park, 2015) contribute to the degeneration of NMJs with advancing age and may also affect ALS. SIRT1 has been shown to influence stress resistance, mitochondrial oxidative phosphorylation, and autophagy (Lagouge et al, 2006; Lee et al, 2008), suggesting that this protein could also impact NMJ degeneration during normal aging and neuromuscular disease. Supporting this possibility, resveratrol was recently shown to slow age‐induced degeneration of NMJs in mice (Stockinger, Maxwell, Shapiro, deCabo, & Valdez, 2017).…”

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

“…Skeletal muscle mitochondrial function (Yamamoto et al ., 2011), mitochondrial biogenesis (Irrcher et al ., 2003), and resistance to oxidative stress (Nishiyama et al ., 1998; Fisher‐Wellman et al ., 2009; Ryan et al ., 2010) were also examined, as these mechanisms mediate exercise performance (Rockl et al ., 2007). The SIRT1, FOXO3a, and MEK pathways, key to mitochondrial biogenesis and protection against oxidative stress, were also examined (Wu et al ., 1999; Lagouge et al ., 2006; Gurd et al ., 2009; Menzies et al ., 2013; Li et al ., 2015; Smith et al ., 2015). As one of the most potent mechanisms limiting longevity is increased oxidative stress (Gemma et al ., 2007), MnSOD levels were examined and exercise was examined in AC5 KO mice mated with MnSOD heterozygous ( MnSOD +/− ) mice.…”