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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学调节机制

基本信息

批准号：
10464664
负责人：
Kayleigh Marie Voos
金额：
$ 3.39万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464664
关键词：
ANK2 gene Aging Binding Biochemical Bioenergetics Biogenesis Biological Biological Assay Calcium Cardiometabolic Disease Cardiovascular Diseases Cell Adhesion Molecules Cell Respiration Cellular biology Complement Complex Cytoskeletal Proteins Cytoskeleton Data Deficiency Diseases Diabetes Mellitus Disease 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 base cell type cost defined contribution endurance exercise energy balance exercise capacity extracellular flexibility genetic variant genome editing in vivo insight insulin regulation insulin sensitivity mouse model novel receptor release of sequestered calcium ion into cytoplasm skeletal muscle metabolism stressor 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.

项目总结