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SWELL1-LRRC8 mediated regulation of skeletal muscle function and metabolism

SWELL1-LRRC8 介导的骨骼肌功能和代谢调节

基本信息

批准号：
10305237
负责人：
Rajan Sah
金额：
$ 43.78万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-20 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10305237
关键词：
Adrenal Cortex Hormones Aerobic Aging Amino Acids Anions Biochemical Biogenesis CRISPR screen CRISPR/Cas technology Cell membrane Chronic Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Denervation Diabetes Mellitus Diabetes prevention Disease Disuse Atrophy Equilibrium FRAP1 gene Fiber Fluorescence Microscopy GLUT 4 protein Gene Expression Generations Genes Genetic Transcription Growth Health Heart Diseases Heart failure Histologic Hour Human Hypertrophy Image Immunoprecipitation In Vitro Insulin Ion Channel Knock-in Mouse Knock-out Label Laboratories Leucine Lysosomes Maintenance Measures Mediating Metabolic Microscopy Mission Mitochondria Modeling Molecular Mus Muscle Muscle Fibers Muscle function National Institute of Diabetes and Digestive and Kidney Diseases Nutrient Obesity Obesity associated disease Paralysed Pathway interactions Proto-Oncogene Proteins c-akt Protons Publishing Reagent Recovery Regulation Research Resolution Role Signal Pathway Signal Transduction Skeletal Muscle Societies Soleus Muscle Stretching Swelling Techniques Testing Tissues Training aging population arm base cancer cachexia defined contribution detection of nutrient exercise capacity experimental study growth factor receptor-bound protein 2 in vivo innovation insight knowledge base mTOR Signaling Pathway membrane model mortality muscle form muscle metabolism muscle physiology mutant novel obesity prevention overexpression patch clamp response skeletal skeletal muscle growth skeletal muscle wasting therapeutic target treadmill treadmill training uptake vacuolar H+-ATPase

项目摘要

Project Summary Maintenance of muscle mass is known to be beneficial in the prevention of obesity and obesity-related diseases such as diabetes and heart disease, in addition to promoting overall health of our aging population. Skeletal muscle atrophy is associated with cancer (cachexia), heart failure, chronic corticosteroid use, paralysis or denervation (disuse atrophy), aging, contributing to poor metabolic health, and increased mortality. Accordingly, a deeper understanding of the molecular mechanisms that regulate skeletal muscle maintenance, growth and function is critical for human health. We recently showed that, in skeletal muscle, SWELL1 is required for maintaining AKT-mTOR signaling, normal muscle fiber size, exercise capacity, force generation, adiposity and systemic glycemia, thereby revealing a novel role for a SWELL1-AKT-mTOR signaling axis in skeletal muscle physiology. Furthermore, our group now has published and unpublished biochemical, patch-clamp and imaging evidence that SWELL1 channel complexes are also expressed and functional in lysosomes (Lyso-SWELL1) – a notion also supported by a recent unbiased CRISPR screen. Given that lysosomes are signaling hubs that integrate nutrient sensing and AKT-mTOR signaling, we hypothesize that SWELL1-LRRC8 channels co-regulate plasma membrane PI3K-AKT signaling and lysosome centered nutrient-mTOR signaling. To test this hypothesis, we combine our unique reagents and expertise in SWELL1 signaling with the those of the Diwan (lysosomal signaling), Xu (lysosomal patch-clamp), and Meyer (skeletal muscle physiology) laboratories. Our objective is to understand the dual mechanisms of plasma membrane SWELL1 signaling and lysosomal SWELL1 (Lyso-SWELL1) nutrient sensing in skeletal muscle and its contribution to skeletal muscle growth and function. The rationale for these studies is that delineating the molecular mechanisms of skeletal muscle SWELL1-AKT-mTOR signaling will advance our understanding of novel, fundamental mechano-signaling and nutrient sensing mechanisms that regulate skeletal muscle growth and function. We propose the following AIMs: · AIM#1: Delineate the mechanisms of plasma membrane versus lysosomal SWELL1 signaling to AKT- mTOR signaling in skeletal muscle cells. These studies will test a novel paradigm for cellular nutrient sensing by a lysosomal ion channel signaling complex in vitro, setting the stage for in vivo experiments. · AIM#2: Examine the contribution of SWELL1 signaling to aerobic capacity, skeletal muscle growth, and force generation in vivo with training and with aging. These studies will define the contributions of SWELL1 signaling to skeletal muscle growth and signaling in vivo, and with aging.

项目总结