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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要亚膜细胞骨架相关蛋白锚蛋白-B (AnkB) 的人类变体已被鉴定为携带这些人类变异的小鼠存在糖尿病、肥胖和心脏代谢疾病的危险因素。多种代谢组织（包括骨骼肌 (SKM)）缺乏，并导致年龄依赖性肥胖虽然 SKM 是 AnkB 缺乏的主要目标，但 AnkB 是如何促成的。 SKM 细胞代谢和能量能力的调节，以及 AnkB 的 SKM 特定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) 驻留蛋白促进线粒体-ER 接触位点的形成我推测 AnkB 的这种功能对于两个细胞器之间的钙转移至关重要。维持线粒体稳态以及适当的骨骼肌代谢和生物能学。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程度第二个目标将定义线粒体-内质网接触位点的形成和线粒体钙通量。 AnkB 对 SKM 细胞呼吸的贡献以及 SKM 的生物能量能力。为 AnkB 在骨骼肌代谢中的新作用提供机制和功能见解，该作用可能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，此外，通过拟议的工作，我将发现新颖的内容。 AnkB 变异的病理生理机制将进一步解释它们对代谢疾病的贡献。