A mechanism of skeletal muscle ER-mitochondria interaction and bioenergetics modulation

项目总结 亚膜细胞骨架相关蛋白ankyrin-B(AnkB)中的人类变体已被鉴定为 糖尿病、肥胖和心脏代谢性疾病的危险因素。携带这些人类变异体的小鼠有AnkB 包括骨骼肌(SKM)在内的多种代谢组织缺乏，并发展为年龄相关性肥胖 全身性血糖处理不当。虽然SKM是AnkB缺乏症的主要靶点，但AnkB如何在 SKM细胞代谢和能量能力的调节以及AnkB在促进SKM的特异性作用中的作用 全身性代谢动态平衡尚未阐明。 这项研究的目标是检验AnkB与线粒体和AnkB形成复合体的总体假设 内质网驻留蛋白促进线粒体-内质网接触部位的形成 以及两个细胞器之间的钙转移。我假设AnkB的这一功能对于 维持线粒体动态平衡，维持适当的骨骼肌代谢和生物能量学。 第一个目标将定义AnkB如何与骨骼肌中的线粒体相互作用及其贡献的程度 与线粒体-内质网接触部位的形成和线粒体钙通量有关。第二个目标将定义 AnkB对SKM细胞呼吸的贡献及SKM的生物能能。这些研究将 提供对AnkB在骨骼肌代谢中的新作用的机制和功能的见解，该作用可能 转化为具有高能量需求的其他类型的细胞，并可能与生理过程有关， 包括对运动和衰老的适应。此外，通过提议的工作，我将发现小说 AnkB变异的病理生理学机制将进一步解释它们在代谢性疾病中的作用。

PROJECT SUMMARY Human variants in the submembrane cytoskeleton-associated protein ankyrin-B (AnkB) have been identified as risk factors for diabetes, obesity and cardiometabolic diseases. Mice harboring these human variants have AnkB deficiency in multiple metabolic tissues, including skeletal muscle (SKM), and develop age-dependent obesity and systemic glucose mishandling. While SKM is a primary target of AnkB deficiency, how AnkB contributes to the regulation of SKM cellular metabolism and energetic capacity, and AnkB’s SKM-specific roles in promoting systemic metabolic homeostasis have not been elucidated. The goal of this study is to test the overarching hypothesis that AnkB forms a complex with mitochondria and endoplasmic reticulum (ER) resident proteins to promote the formation of mitochondria-ER contact sites and calcium transfer between the two organelles. I postulate that this function of AnkB is essential for maintaining mitochondria homeostasis and for proper skeletal muscle metabolism and bioenergetics. The first aim will define how AnkB interacts with mitochondria in skeletal muscle and the extent of its contribution to the formation of mitochondria-ER contact sites and to mitochondria calcium flux. The second aim will define the contribution of AnkB to SKM cellular respiration and the bioenergetic capacity of SKM. These studies will provide mechanistic and functional insights into a novel role of AnkB in skeletal muscle metabolism that may translate to other cell types with high energetic demand, and might be relevant to physiological processes, including adaptation to exercise and ageing. Moreover, through the proposed work I will uncover novel pathophysiological mechanisms of AnkB variants that will further explain their contribution to metabolic diseases.