Regulation of mitochondrial bioenergetics in striated muscle

由于肌肉生理学在新陈代谢、综合生理学、运动学等领域的重要性，横纹肌中线粒体生物能量学的调控受到了广泛的关注。经典模型捕捉到了调节线粒体和肌肉收缩的基本反馈/前馈回路，而一个新兴的模型则暗示细胞骨架是线粒体生物能量学的独特调节器。与我们发现调控线粒体生物能量学的新机制及其与肌肉功能的关系的长期目标一致，我们建议研究特定的细胞骨架-线粒体相互作用如何调节横纹肌力、质量和质量。 为了解决这一假设，我们的五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学的影响，这是否改变这些细胞骨架成分和调节ADP通透性的外膜电压依赖性阴离子通道(主要生物能量学控制器)之间的特定相互作用，以及细胞外基质(ECM)中的VI型胶原和层粘连蛋白对ECM的细胞黏附如何改变调节生物能量学的微管-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架-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细胞中的微管、波形蛋白、VI型胶原和层粘连蛋白，或来自啮齿动物的单个纤维，这些纤维从遗传学或药理学上具有修饰这些蛋白质的目标。 我的受训人员和我已经证明，我们拥有必要的基础设施和专业知识来开展核心技术，长期的合作者在某些方法上提供必要的支持，以确保对这些研究采取跨学科的方法。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涉及许多领域，基础研究将为众多研究方向提供洞察力。该计划还将为6名研究生和5名本科生提供生理学、线粒体生物能量学、细胞和分子生物学、生物化学和药理学领域的全面和多样化的培训经验，以及在所有职业领域(包括工业、学术界和政府)所追求的可转移的领导、项目管理、沟通和知识传播方面的技能。

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.