Energy sensing in skeletal muscle: focus on mitochondrial metabolic adaptation

骨骼肌能量传感：关注线粒体代谢适应

• 批准号: RGPIN-2015-04286
• 负责人: Kane, Daniel
• 金额: $ 1.75万
• 依托单位: St. Francis Xavier University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=679693
• 关键词: Energy; sensing; skeletal; muscle; focus

Background: Often referred to as the "powerhouses of the cell," mitochondria have long been recognized as key producers of ATP, the cellular metabolic currency. In recent decades, however, mitochondria have increasingly been implicated in many additional cell processes, ranging from cellular calcium homeostasis to even cell death. In skeletal muscle, the energetic demands placed on the cell can fluctuate rapidly as an organism transitions between rest and exercise. Some of the purturbations in cellular redox state that occur in muscle with exercise are known to constitute a stimulus for acute alterations in mitochondrial function, as well as mitochondrial turnover and biogenesis. ******Objectives: The purpose of this research program is to determine the effects of increased energy demand associated with physical exercise on skeletal muscle mitochondrial function, with a focus on redox biology and mitochondrial energetics. It is proposed that the enzyme quinone reductase 2 (QR2) acts in a feedback loop mediated by the redox-sensitive transcription factor Nrf2, in response to physical activity, to boost mitochondrial content and activity in skeletal muscle The net result of this regulatory loop is more robust mitochondria, capable of mitigating oxidative stress and cell death, in addition to increased ATP resynthesis. In order to meet objectives, the program will address the following questions: 1) How does exercise training alter mitochondrial metabolism of specific substrates/compounds in skeletal muscle? 2) What are the mechanisms by which exercise-associated alterations in skeletal muscle mitochondrial function exert their effects on mitigating oxidative stress and cell death, in addition to increased ATP production?******Methodology: To achieve the research program objectives, we will use a combination of methodological approaches, ranging from standard molecular biology techniques, to state-of-the-art functional measurements on small skeletal muscle samples from rats (exercise-trained versus untrained) and mice (Nrf2 and QR2 null transgenic models). In so doing, the cellular localization and expression levels of both Nrf2 and QR2 will be determined in different skeletal muscle types (i.e., oxidative versus glycolytic) following exercise. The functional consequences of altered Nrf2 and QR2 content and activity in skeletal muscle following exercise will be determined. ******Impact: The expected short-term impact of this research include a better understanding of the mechanisms by which specific regulators (e.g., QR2) of mitochondrial redox biology in processes previously ignored as being fundamental to maintaining cellular energy and redox homeostasis. In the long-term, this program will expose critical regulators of mitochondrial bioenergetics which have been missing from fundamental models of regulating cell function.******

背景：线粒体通常被称为“细胞的发动机”，长期以来一直被认为是细胞代谢货币三磷酸腺苷的关键生产者。然而，近几十年来，线粒体越来越多地参与了许多额外的细胞过程，从细胞钙稳态到甚至细胞死亡。在骨骼肌中，当有机体在休息和运动之间转换时，施加在细胞上的能量需求可以迅速波动。运动中肌肉细胞氧化还原状态的一些扰动被认为是线粒体功能以及线粒体周转和生物发生的急性改变的刺激因素。*目的：本研究的目的是确定与运动相关的能量需求增加对骨骼肌线粒体功能的影响，重点是氧化还原生物学和线粒体能量学。有人提出，在氧化还原敏感的转录因子Nrf2介导的反馈环中，QR2作用于体力活动，提高骨骼肌中线粒体的含量和活性。这一调控环的最终结果是线粒体更健壮，能够减轻氧化应激和细胞死亡，并增加ATP的再合成。为了达到目标，该计划将解决以下问题：1)运动训练如何改变骨骼肌中特定底物/化合物的线粒体代谢？2)运动相关的骨骼肌线粒体功能改变除了增加ATP的产生外，还通过什么机制起到缓解氧化应激和细胞死亡的作用？*方法：为了实现研究计划的目标，我们将使用多种方法的组合，从标准的分子生物学技术，对来自大鼠(运动训练与未训练)和小鼠(Nrf2和QR2零转基因模型)的小骨骼肌样本进行最先进的功能测量。这样，Nrf2和QR2的细胞定位和表达水平将在运动后不同类型的骨骼肌(即氧化和糖酵解)中确定。运动后骨骼肌中Nrf2和QR2含量和活性改变的功能后果将得到确定。*影响：这项研究的预期短期影响包括更好地了解线粒体氧化还原生物学的特定调节因子(例如QR2)在以前被忽视的过程中对维持细胞能量和氧化还原动态平衡至关重要的机制。从长远来看，这个项目将揭露线粒体生物能量学的关键调节器，这些调节器一直没有出现在调节细胞功能的基本模型中。