Regulation of mitochondrial bioenergetics in striated muscle

横纹肌线粒体生物能的调节

• 批准号: RGPIN-2019-06687
• 负责人: Perry, Christopher
• 金额: $ 2.91万
• 依托单位: York University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=757807
• 关键词: Regulation; mitochondrial; bioenergetics; striated; muscle

The regulation of mitochondrial bioenergetics in striated muscle has received much attention given the importance of muscle physiology to fields like metabolism, integrative physiology, mobility etc. While classic models capture fundamental feedback/feedforward loops that regulate mitochondrial and muscle contraction, an emerging model has implicated the cytoskeleton as a unique regulator of mitochondrial bioenergetics. Consistent with our long-term objectives to uncover novel mechanisms regulating mitochondrial bioenergetics and their relationship with muscle function, we propose to investigate how specific cytoskeletal-mitochondrial interactions modulate striated muscle force, mass and quality. To address this hypothesis, our 5 year plan aims to achieve the following goals: Goal #1: Define how the cytoskeletal components regulate mitochondrial bioenergetics. In vitro and in vivo studies will investigate the effects of altering microtubule and intermediate filament architecture on mitochondrial bioenergetics, whether this alters specific interactions between these cytoskeletal components and the outer membrane voltage dependent anion channel which regulates ADP permeability (a master bioenergetic controller), and how collagen VI in the extracellular matrix (ECM) and cell adhesion to ECM by laminin alters a microtubule-mitochondrial axis of regulating bioenergetics. Goal #2: Understand how cytoskeletal regulation of mitochondrial bioenergetics influences muscle function. In vitro and in vivo studies will determine how the above manipulations of cytoskeletal-mitochondrial interactions regulate muscle force production, quality (necrosis, fibrosis) and mass/atrophy. For both overall Goals, in vitro and in vivo studies will manipulate microtubule, vimentin, collagen VI and laminin in primary cells or single fibres from rodents that are genetically or pharmacologically targeted to modify these proteins. My trainees and I have demonstrated that we have the necessary infrastructure and expertise to conduct the core techniques with long-standing collaborators providing the necessary support on certain methods to ensure the interdisciplinary approach to these studies. The proposed aims will provide novel insight into the basic mechanisms by which cytoskeletal components regulate mitochondrial bioenergetics and striated muscle function. Given that both mitochondrial bioenergetics and striated muscle physiology are connected to many fields, the foundational studies will provide insight to numerous research directions. This plan will also provide comprehensive and diverse training experiences to 6 graduate and >5 undergraduate HQP in the areas of physiology, mitochondrial bioenergetics, cellular and molecular biology, biochemistry, and pharmacology, in addition to transferable skills in leadership, project management, communication and knowledge dissemination that are sought after in all career sectors including industry, academia and government.

鉴于肌肉生理学在代谢、综合生理、运动等领域的重要性，横纹肌线粒体生物能量学的调控受到了广泛关注。虽然经典模型捕获了调节线粒体和肌肉收缩的基本反馈/前馈循环，但一个新兴模型暗示细胞骨架是线粒体生物能量学的独特调节剂。我们的长期目标是揭示调节线粒体生物能量的新机制及其与肌肉功能的关系，我们建议研究特定的细胞骨骼-线粒体相互作用如何调节横纹肌的力量、质量和质量。为了解决这一假设，我们的5年计划旨在实现以下目标：目标#1：定义细胞骨架成分如何调节线粒体生物能量学。体外和体内研究将探讨改变微管和中间丝结构对线粒体生物能量的影响，这是否会改变这些细胞骨架成分与调节ADP渗透性的外膜电压依赖阴离子通道之间的特定相互作用（一种主要的生物能量控制器）。以及细胞外基质（ECM）中的胶原VI和层粘连蛋白对ECM的粘附如何改变调节生物能量的微管-线粒体轴。目标2：了解线粒体生物能量学的细胞骨架调节如何影响肌肉功能。体外和体内研究将确定上述细胞骨骼-线粒体相互作用的操作如何调节肌肉力量的产生、质量（坏死、纤维化）和质量/萎缩。对于这两个总体目标，体外和体内研究将操纵原代细胞或来自啮齿动物的单个纤维中的微管、vimentin、VI型胶原和层粘连蛋白，以修饰这些蛋白质。我和我的学员已经证明，我们有必要的基础设施和专业知识来实施核心技术，长期合作伙伴提供必要的支持，以确保这些研究的跨学科方法。提出的目标将为细胞骨架成分调节线粒体生物能量学和横纹肌功能的基本机制提供新的见解。鉴于线粒体生物能量学和横纹肌生理学都与许多领域有关，基础研究将为许多研究方向提供见解。该计划还将为6名研究生和50名本科生在生理学、线粒体生物能量学、细胞和分子生物学、生物化学和药理学等领域提供全面和多样化的培训经验，以及在领导、项目管理、沟通和知识传播方面的可转移技能，这些技能在包括工业、学术界和政府在内的所有职业领域都受到欢迎。