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Effects of resveratrol and SIRT1 on PGC-1? activity and mitochondrial biogenesis: a reevaluation.

ABSTRACT: It has been reported that feeding mice resveratrol activates AMPK and SIRT1 in skeletal muscle leading to deacetylation and activation of PGC-1?, increased mitochondrial biogenesis, and improved running endurance. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1? deacetylation on mitochondrial biogenesis in muscle. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on mitochondrial protein levels in muscle. High concentrations of resveratrol lowered ATP concentration and activated AMPK in C?C?? myotubes, resulting in an increase in mitochondrial proteins. Knockdown of SIRT1, or suppression of SIRT1 activity with a dominant-negative (DN) SIRT1 construct, increased PGC-1? acetylation, PGC-1? coactivator activity, and mitochondrial proteins in C?C?? cells. Expression of a DN SIRT1 in rat triceps muscle also induced an increase in mitochondrial proteins. Overexpression of SIRT1 decreased PGC-1? acetylation, PGC-1? coactivator activity, and mitochondrial proteins in C?C?? myotubes. Overexpression of SIRT1 also resulted in a decrease in mitochondrial proteins in rat triceps muscle. We conclude that, contrary to some previous reports, the mechanism by which SIRT1 regulates mitochondrial biogenesis is by inhibiting PGC-1? coactivator activity, resulting in a decrease in mitochondria. We also conclude that feeding rodents resveratrol has no effect on mitochondrial biogenesis in muscle.

SUBMITTER: Higashida K

PROVIDER: S-EPMC3706311 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Effects of resveratrol and SIRT1 on PGC-1α activity and mitochondrial biogenesis: a reevaluation.

Higashida Kazuhiko K Kim Sang Hyun SH Jung Su Ryun SR Asaka Meiko M Holloszy John O JO Han Dong-Ho DH

PLoS biology 20130709 7

It has been reported that feeding mice resveratrol activates AMPK and SIRT1 in skeletal muscle leading to deacetylation and activation of PGC-1α, increased mitochondrial biogenesis, and improved running endurance. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1α deacetylation on mitochondrial biogenesis in muscle. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on mitochondrial protein levels in muscle. High concentrations of resv ...[more]

PMID: 23874150

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Project description:Rationale: Potential adverse effects of fluoride on neurodevelopment has been extensively explored and mitochondria have been recognized as critical targets. Mitochondrial biogenesis serves a crucial role in maintaining mitochondrial homeostasis and salubrious properties of resveratrol (RSV) has been well-defined. However, the molecular mechanisms governing mitochondrial biogenesis in developmental fluoride neurotoxicity remain unclear and the related therapeutic dietary agent is lacking. Methods: In vitro neuroblastoma SH-SY5Y cells and in vivo Sprague-Dawley rat model of developmental fluoride exposure were adopted. A total population of 60 children under long-term stable fluoride exposure were also recruited. This work used a combination of biochemical and behavioral techniques. Biochemical methods included analysis of mitochondrial function and mitochondrial biogenesis, as well as mRNA and protein expression of mitochondrial biogenesis signaling molecules, including silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Behavioral studies investigated spatial learning and memory ability of rats. Results: Both in vivo and in vitro experiments showed that sodium fluoride (NaF) caused mitochondrial dysfunction and impaired mitochondrial biogenesis. Also, NaF elevated SIRT1 levels and suppressed SIRT1 deacetylase activity along with decreased levels of PGC-1?, NRF1 and TFAM, suggestive of dysregulation of mitochondrial biogenesis signaling molecules. Moreover, enhancement of mitochondrial biogenesis by TFAM overexpression alleviated NaF-induced neuronal death through improving mitochondrial function in vitro. Further in vivo and in vitro studies identified RSV, the strongest specific SIRT1 activator, improved mitochondrial biogenesis and subsequent mitochondrial function to protect against developmental fluoride neurotoxicity via activating SIRT1-dependent PGC-1?/NRF1/TFAM signaling pathway. Noteworthy, epidemiological data indicated intimate correlations between disturbed circulating levels of mitochondrial biogenesis signaling molecules and fluoride-caused intellectual loss in children. Conclusions: Our data suggest the pivotal role of impaired mitochondrial biogenesis in developmental fluoride neurotoxicity and the underlying SIRT1 signaling dysfunction in such neurotoxic process, which emphasizes RSV as a potential therapeutic dietary agent for relieving developmental fluoride neurotoxicity.

Dataset Information

Effects of resveratrol and SIRT1 on PGC-1? activity and mitochondrial biogenesis: a reevaluation.

Publications

Effects of resveratrol and SIRT1 on PGC-1α activity and mitochondrial biogenesis: a reevaluation.

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