Contrary to previous reports we find that deacetylation by SIRT1 decreases PGC-1α activity and results in a decrease in mitochondria moreover we show that the increase in mitochondria induced in cultured muscle cells by a high resveratrol concentration is due to the toxic activation of AMPK and, in turn, PGC-1α. In these rodents, the bioavailability of oral resveratrol is low, and the resulting plasma level of resveratrol is far below the concentration required to activate AMPK. We find that feeding rats or mice large amounts of resveratrol did not increase muscle mitochondria. Here we further analyze the adaptive response of muscle mitochondria to resveratrol treatment to see if it mimics the response to endurance exercise. It has also been reported that feeding resveratrol to mice increases muscle mitochondria and results in improved running endurance. SIRT1 is then thought to deacetylate and activate the transcriptional coactivator PGC-1α, which in turn stimulates mitochondrial biogenesis. This has been attributed to the activation of the deacetylase SIRT1 either directly by resveratrol or indirectly via the activation of AMP-activated protein kinase (AMPK). Studies on cultured muscle cells have shown that treatment with resveratrol, a chemical famously found in the skin of red grapes, stimulates the manufacture of new mitochondria. We also conclude that feeding rodents resveratrol has no effect on mitochondrial biogenesis in muscle. We conclude that, contrary to some previous reports, the mechanism by which SIRT1 regulates mitochondrial biogenesis is by inhibiting PGC-1α coactivator activity, resulting in a decrease in mitochondria. Overexpression of SIRT1 also resulted in a decrease in mitochondrial proteins in rat triceps muscle. Overexpression of SIRT1 decreased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C 2C 12 myotubes. Expression of a DN SIRT1 in rat triceps muscle also induced an increase in mitochondrial proteins. Knockdown of SIRT1, or suppression of SIRT1 activity with a dominant-negative (DN) SIRT1 construct, increased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C 2C 12 cells. High concentrations of resveratrol lowered ATP concentration and activated AMPK in C 2C 12 myotubes, resulting in an increase in mitochondrial proteins. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on mitochondrial protein levels in muscle. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1α deacetylation on mitochondrial biogenesis in muscle. 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.
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