Regulation of mitochondrial bioenergetics in striated muscle

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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.