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

SIRT1 的翻译后调控：激活和亚细胞区域对骨骼肌线粒体生物合成的影响

• 批准号: 402635-2011
• 负责人: Gurd, Brendon
• 金额: $ 2.62万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=573345
• 关键词: Post; translational; regulation; SIRT1; impact

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.

骨骼肌产生力量的能力在一定程度上取决于肌肉内线粒体产生能量的能力。因此，骨骼肌中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。 线粒体含量的变化是由于一种名为过氧化物酶体增殖物激活受体-1α(PGC-1α)的酶的转录活性发生变化。PGC-1α的活性被认为是由另一种称为沉默交配型信息调节2同源1(SIRT1)的酶来调节的，然而SIRT1在骨骼肌线粒体含量增加中的作用目前尚不清楚。因此，我们提出了一项研究计划，将研究SIRT1在运动诱导的PGC-1α激活和线粒体含量增加中的作用。我们将使用尖端分子技术来检测单轮运动和运动训练后SIRT1活性的变化。我们还将通过测量运动后SIRT1分子结构的变化来研究SIRT1的激活机制。此外，我们将尝试确定当骨骼肌中SIRT1的存在高于或低于正常时，运动对线粒体内容的影响。这将通过一种名为转染法的技术上调或下调SIRT1 ensyme的含量来实现。最后，我们将试图通过同时测量SIRT1活性和PGC-1α激活的变化来证实SIRT1和PGC-1α在人类骨骼肌中的可能关系。 虽然上面列出的一些技术需要使用动物模型，但我们的目标是了解SIRT1在人类骨骼肌中的作用，并在可能的情况下使用人类受试者。该项目将加深我们对骨骼肌中线粒体含量调控的了解，并将允许培训众多高素质的分子生物学和健身评估/运动处方方面的人员。