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

骨骼肌 ER-线粒体相互作用和生物能调节机制

• 批准号: 10766531
• 负责人: Kayleigh Marie Voos
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10766531
• 关键词: ANK2 gene; Aging; Binding; Biochemical; Bioenergetics; Biogenesis; Biological; Biological Assay; Calcium; Cardiometabolic Disease; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Respiration; Cells; Cellular biology; Complement; Complex; Cytoskeletal Proteins; Cytoskeleton; Data; Deficiency Diseases; Diabetes Mellitus; Disease; Dissociation; Endoplasmic Reticulum; Exercise; Exhibits; Genetic Transcription; Glucose; Goals; Health; Homeostasis; Human; Human Genetics; Human body; ITPR1 gene; Impairment; Inositol; Insulin; Ion Channel; Knock-in Mouse; Knockout Mice; Label; Lead; Link; Measures; Membrane Microdomains; Membrane Transport Proteins; Metabolic; Metabolic Diseases; Metabolism; Microscopy; Mitochondria; Molecular; Mus; Muscle Cells; Muscle Fibers; Myopathy; Nature; Neurons; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Organelles; Oxygen Consumption; Pathway interactions; Physiological Processes; Physiology; Positioning Attribute; Production; Proteins; Publishing; Regulation; Reporting; Resolution; Respiration; Risk Factors; Role; Signal Transduction; Site; Skeletal Development; Skeletal Muscle; Stress; Structure; Techniques; Testing; Tissues; Training; Translating; Transmission Electron Microscopy; Variant; Work; age related; cell type; cost; defined contribution; endurance exercise; energy balance; exercise capacity; extracellular; flexibility; genetic variant; genome editing; in vivo; inorganic phosphate; insight; insulin regulation; insulin sensitivity; mouse model; novel; receptor; release of sequestered calcium ion into cytoplasm; skeletal muscle metabolism; stressor; superresolution microscopy; ultra high resolution; western diet

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.

项目摘要 膜下细胞凋亡相关蛋白锚蛋白-B（AnkB）的人类变体已被鉴定为 糖尿病、肥胖和心脏代谢疾病的危险因素。携带这些人类变体的小鼠具有AnkB 缺乏多种代谢组织，包括骨骼肌（SKM），并发展成年龄依赖性肥胖 和全身葡萄糖处理不当虽然SKM是AnkB缺陷的主要靶点，但AnkB如何有助于 SKM细胞代谢和能量能力的调节，以及AnkB在促进SKM特异性作用中的作用 全身代谢稳态尚未阐明。 本研究的目的是检验AnkB与线粒体形成复合物的总体假设， 内质网（ER）驻留蛋白，以促进形成内质网-ER接触位点 和钙离子在两个细胞器之间的转移。我假设AnkB的这种功能对于 维持线粒体稳态和适当的骨骼肌代谢和生物能量学。 第一个目标是确定AnkB如何与骨骼肌中的线粒体相互作用及其贡献的程度 对线粒体钙流的影响。第二个目标将定义 AnkB对SKM细胞呼吸的贡献和SKM的生物能容量。这些研究将 为AnkB在骨骼肌代谢中的新作用提供了机制和功能方面的见解， 转化为具有高能量需求的其他细胞类型，并且可能与生理过程相关， 包括对运动和衰老的适应。此外，通过拟议的工作，我将揭示小说 AnkB变异的病理生理机制，将进一步解释其对代谢疾病的贡献。