IS NITRIC OXIDE A CENTRAL REGULATOR OF EXERCISE-INDUCED SKELETAL MUSCLE MITOCHONDRIAL BIOGENESIS?

线粒体是细胞的能量产生部分，也是新陈代谢的主要控制者。现在有很好的证据表明，肌肉线粒体大小减少会导致糖尿病。运动对糖尿病患者有好处，部分原因是增加了肌肉线粒体的生成(线粒体生物发生)。不幸的是，人们对运动后增加肌肉线粒体生物发生的机制知之甚少。最近的研究表明，肌肉在运动过程中产生的一种气体一氧化氮(NO)在脂肪细胞的线粒体生物发生中发挥着作用。该项目将确定NO是否是运动诱导的骨骼肌线粒体生物发生的中央调节因子。如果我们发现一氧化氮增加了肌肉中线粒体的生物生成，那么旨在模仿这些运动效应的药物可能会预防或改善糖尿病。我们将首先确定改变在培养中生长的肌肉细胞中NO水平的特定药物治疗是否会改变线粒体的生物发生。这些结果将有助于我们阐明NO在线粒体生物发生中的作用。然而，很难直接检测运动对培养细胞的影响。因此，进一步的研究将使用现实生活中的模型，如已经锻炼过的啮齿动物，来研究一氧化氮的作用和锻炼对线粒体生物发生的影响。我们将喂食一种药物来降低正常大鼠的NO水平；并使用基因改变为缺乏NO的小鼠来确定这些治疗是否会减少耐力运动后通常可以看到的线粒体生物合成。此外，由于线粒体生物发生缺陷对糖尿病人类有如此重要的影响，我们将利用人类来检查2型糖尿病患者或耐力训练运动员骨骼肌中NO水平的差异是否与线粒体生物发生相关。最后，我们将给2型糖尿病患者注射一种增加肌肉中NO的药物，以确定它是否也增加了线粒体的生物生成。

Mitochondria are the energy producing parts of the cell and are the major controllers of metabolism. There is now good evidence that reduced muscle mitochondrial size contributes to diabetes. Exercise is good for diabetics due partly to increasing muscle mitochondrial production (mitochondrial biogenesis). Unfortunately, little is known about the mechanisms involved in increased muscle mitochondrial biogenesis following exercise. It has been shown recently that nitric oxide (NO), a gas made by muscle during exercise, plays a role in mitochondrial biogenesis in fat cells. This project will determine whether NO is a central regulator of exercise-induced mitochondrial biogenesis in skeletal muscle. If we find that NO increases mitochondrial biogenesis in muscle, drugs designed to mimic these exercise effects may prevent or improve diabetes. We will firstly establish if specific drug treatments that alter NO levels in muscle cells grown in culture alter mitochondrial biogenesis. These results will help us to clarify the role of NO in mitochondrial biogenesis. However, it is difficult to directly examine the effects of exercise in cultured cells. Therefore, further studies will then use real life models such as rodents that have been exercised to examine the role of NO and exercise on mitochondrial biogenesis. We will feed a drug to decrease NO levels in normal rats; and use mice, genetically altered to be lacking in NO to determine if these treatments decrease mitochondrial biogenesis that is normally seen following endurance exercise. Furthermore, since defects in mitochondrial biogenesis have such an important impact on diabetic humans, we will use humans to examine if differences in NO levels in skeletal muscle among type 2 diabetics or endurance-trained athletes correlate with mitochondrial biogenesis. Finally, we will infuse a drug into type 2 diabetics that increases NO in muscle to determine if it also increases mitochondrial biogenesis.