Regulation of mitochondrial bioenergetics in striated muscle

横纹肌中线粒体生物能量的调节受到了广泛关注，因为肌肉生理学对代谢，综合生理学，流动性等领域的重要性。虽然经典模型捕获了调节线粒体和肌肉收缩的基本反馈/前馈回路，但一种新兴的模型涉及细胞骨架作为线粒体生物能量的独特调节剂。与我们的长期目标一致，发现新的机制调节线粒体生物能量学及其与肌肉功能的关系，我们建议研究特定的细胞质-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。 体外和体内研究将研究改变微管和中间丝结构对线粒体生物能量学的影响，这是否改变了这些细胞骨架成分与调节ADP渗透性的外膜电压依赖性阴离子通道之间的特异性相互作用（主生物能量控制器），以及细胞外基质（ECM）中的胶原VI和层粘连蛋白对ECM的细胞粘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细胞质-线粒体相互作用的上述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来自啮齿动物的原代细胞或单纤维中的微管、波形蛋白、胶原VI和层粘连蛋白，所述原代细胞或单纤维被遗传或生物学靶向以修饰这些蛋白质。 我和我的学员已经证明，我们拥有必要的基础设施和专业知识来进行核心技术，长期合作者为某些方法提供必要的支持，以确保这些研究的跨学科方法。提出的目标将提供新的见解的基本机制，细胞骨架成分调节线粒体生物能量学和横纹肌功能。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>5名本科生HQP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，此外还有领导力，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追捧。

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.