| The histone deacetylase SirT1 has recently been demonstrated to play a pivotal in cellular metabolic sensing. In response to elevations in NAD +, a key cellular metabolite, SirT1 deacetylates and activates proteins that regulate metabolic pathways and mitochondrial biogenesis. The dysregulation of these SirT1 effects can lead to obesity, diabetes, cancer and cardiovascular disease. Using both cell culture and in vivo approaches, we compared the treatment of resveratrol (RSV), an activator of SirT1, to that of exercise to induce mitochondrial biogenesis.;In Chapter 3, we further examined the role of SirT1 in mitochondrial biogenesis through the generation of skeletal muscle-specific SirT1-KO mice. We used voluntary wheel-running exercise, dietary RSV, or a combination of these two treatments to examine role of SirT1 in the induction of mitochondrial biogenesis. These experiments demonstrated that SirT1 plays a modest role in maintaining basal mitochondrial content, and a larger role in preserving mitochondrial function. Voluntary exercise and RSV treatment induced mitochondrial biogenesis in a SirT1-independent manner. However, when RSV and exercise were combined, a SirT1-dependent synergistic effect was evident, leading to the stimulation of mitochondrial biogenesis.;These data uniquely suggest that SirT1 protein is partly responsible for the maintenance of mitochondria in muscle, in addition to lowering mitochondrial ROS generation and lessening the rate of fatigue. In addition, the therapeutic potential of RSV for the induction of mitochondrial biogenesis and function may rely on the presence of a cellular environment created by repeated energy demands.;In Chapter 2, the ability of exercise to induce mitochondrial biogenesis was examined with chronic contractile activity (CCA) of C2C12 mouse myotubes through electrical stimulation. The induction of mitochondrial biogenesis with CCA in C2C12 myotubes was then compared to those treated with RSV, or the combination CCA and RSV. Our results demonstrated that CCA produced a more robust induction than RSV treatment. In addition, the combination of CCA and RSV resulted in a synergistic effect on mitochondrial biogenesis. We found that this synergistic effect may be the result of the combined increase in PGC-1alpha protein by CCA, and the activation of SirT1 by RSV. |
