Mechanisms controlling mitochondrial content and function in skeletal muscle

控制骨骼肌线粒体含量和功能的机制

• 批准号: RGPIN-2016-04838
• 负责人: Gurd, Brendon
• 金额: $ 2.26万
• 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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709246
• 关键词: Mechanisms; controlling; mitochondrial; content; function

The ability of skeletal muscle to generate force is determined, in part, by the ability of mitochondria within muscle to utilize carbohydrates and fats and generate energy. The function 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-1alpha (PGC-1alpha). The activity of PGC-1alpha is proposed to be regulated by another enzyme called Sirtuin 1 (SIRT1) however the role of SIRT1 in increased mitochondrial content via activation PGC-1alpha in skeletal muscle is not fully understood. Another Sirtuin, SIRT3, is also believed to play a role mitochondrial function by helping activate energy production in mitochondria through the activation of PDH. SIRT3 may also play a role in the upregulation of mitochondrial content following exercise training via the activation of LRP130. Neither of these effects of SIRT3 have been examined in skeletal muscle. The proposed research program will examine the role of SIRT1 in exercise induced activation of PGC-1alpha and the importance of SIRT3 in determining mitochondrial function. We will use cutting edge molecular techniques to examine changes in SIRT1 and SIRT3 activity following a single bout of exercise and following exercise training via the activation of LRP130. We will also examine the mechanism(s) by which SIRT1 and SIRT3 alter muscle function by measuring changes in the molecular structure of their targets. The proposed research will impact our understanding of how muscle works, and our understanding of the mechanisms that underlying normal muscle function. We will expand our current knowledge surrounding the roles of SIRT1 and SIRT3 in human skeletal muscle, will potentially provide evidence regarding human physiology that has the potential to directly impact the Canadian population. More specifically, by furthering our understanding of how mitochondrial content and function are controlled in human skeletal muscle our basic research will provide information that can be used by applied scientists to help improve physical fitness and performance as well as health in Canadians. This research program will also provide opportunities for undergraduate and graduate students to learn the research process, while contributing to high quality research.

骨骼肌产生力的能力部分取决于肌肉内线粒体利用碳水化合物和脂肪并产生能量的能力。因此，骨骼肌内线粒体的功能是运动能力、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叫做过氧化物酶体增殖物激活受体γ辅激活因子-1 α（PGC-1 α）的酶的转录活性发生变化。PGC-1 α的活性被认为是由另一种称为Sirtuin 1（SIRT 1）的酶调节的，然而，SIRT 1在骨骼肌中通过激活PGC-1 α增加线粒体含量中的作用尚未完全了解。另一种Sirtuin，SIRT 3，也被认为通过激活PDH来帮助激活线粒体中的能量产生，从而发挥线粒体功能。SIRT 3也可能通过激活LRP 130在运动训练后线粒体含量的上调中发挥作用。 SIRT 3的这些作用都没有在骨骼肌中进行过研究。 这项研究计划将研究SIRT 1在运动诱导的PGC-1 α激活中的作用，以及SIRT 3在决定线粒体功能中的重要性。我们将使用尖端的分子技术来检查SIRT 1和SIRT 3活性在单次运动后以及通过激活LRP 130进行运动训练后的变化。我们还将研究SIRT 1和SIRT 3通过测量其靶分子结构的变化来改变肌肉功能的机制。 这项拟议的研究将影响我们对肌肉如何工作的理解，以及我们对正常肌肉功能潜在机制的理解。 我们将扩大我们目前对SIRT 1和SIRT 3在人类骨骼肌中的作用的了解，将有可能提供有关人类生理学的证据，这些证据有可能直接影响加拿大人口。 更具体地说，通过进一步了解人类骨骼肌中线粒体的含量和功能是如何控制的，我们的基础研究将提供可供应用科学家使用的信息，以帮助改善加拿大人的体能和表现以及健康。 该研究计划还将为本科生和研究生提供学习研究过程的机会，同时有助于高质量的研究。