Post-translational regulation of SIRT1: the impact of activation and subcellular locale on mitochondrial biogenesis in skeletal muscle

骨骼肌产生力量的能力部分取决于肌肉内线粒体产生能量的能力。因此，骨骼肌内线粒体的含量是运动能力、运动耐量和生活质量的重要决定因素。

The ability of skeletal muscle to generate force is determined, in part, by the ability of mitochondria within muscle to generate energy. The content of mitochondria within skeletal muscle is therefore an important determinant of exercise capacity, exercise tolerance, and quality of life. Changes in mitochondrial content occur because of changes in the transcriptional activity of an enzyme called Peroxisome proliferator-activated receptor gamma coactivator-1aplpha (PGC-1alpha). The activity of PGC-1alpha is proposed to be regulated by another enzyme called Silent mating type information regulation 2 homolog 1 (SIRT1) however the role of SIRT1 in increased mitochondrial content in skeletal muscle is not currently clear. Thus we are proposing a research program that will examine the role of SIRT1 in exercise induced activation of PGC-1alpha and increases in mitochondrial content. We will use cutting edge molecular techniques to examine changes in SIRT1 activity following a single bout of exercise and following exercise training. We will also examine the mechanism of SIRT1 activation by measuring changes in the molecular structure of SIRT1 following exercise. In addition we will attempt to determine the effects of exercise on mitochondrial content when the presence of SIRT1 within skeletal muscle is higher than, or lower than, normal. This will be accomplished by upregulating or knocking down the content of SIRT1 ensyme by a technique called transfection. Finally we will attempt to confirm the proposed relationship between SIRT1 and PGC-1alpha in human skeletal muscle by measuring changes in SIRT1 activity and PGC-1alpha activation simultaneously. While some of the techniques listed above require the use of animal models we aim to understand the role of SIRT1 in human skeletal muscle and will use human subjects where possible. This program will further our knowledge of regulation of mitochondrial content in skeletal muscle and will allow for training of numerous highly qualified personnel in both molecular biology and fitness evaluation/exercise prescription.