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：
10618270
负责人：
Rajan Sah
金额：
$ 41.42万
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/10618270
关键词：
Adipocytes Adrenal Cortex Hormones Aerobic Aging Amino Acids Anions Biochemical Biogenesis CRISPR screen CRISPR/Cas technology Cachexia Cell membrane Chronic 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 Malignant Neoplasms Measures Mediating Metabolic Mission Mitochondria Modeling Molecular Mus Muscle Muscle Fibers Muscle function National Institute of Diabetes and Digestive and Kidney Diseases Nutrient Obesity Obesity associated disease Osmosis PIK3CG gene Paralysed Pathway interactions Proto-Oncogene Proteins c-akt Protons Publishing Reagent Recovery Regulation Research Role Signal Transduction Skeletal Muscle Societies Soleus Muscle Stretching Swelling Techniques Testing Tissues Training aging population arm defined contribution detection of nutrient exercise capacity experimental study growth factor receptor-bound protein 2 in vivo innovation insight knowledge base mTOR Signaling Pathway mortality muscle form muscle metabolism muscle physiology mutant novel obesity prevention overexpression patch clamp response skeletal muscle growth skeletal muscle wasting superresolution microscopy 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.

项目摘要众所周知，肌肉质量的维持对预防肥胖症和与肥胖有关的疾病有益除了促进我们老龄化人群的整体健康外，例如糖尿病和心脏病。骨骼肌肉萎缩与癌症（恶病质），心力衰竭，慢性皮质类固醇使用，麻痹或改造（废除萎缩），衰老，导致代谢不良和死亡率增加。根据对调节骨骼肌维持，生长和的分子机制有更深入的了解功能对于人类健康至关重要。我们最近表明，在骨骼肌中，维持Akt-MTOR信号，正常需要swell1 肌肉纤维尺寸，运动能力，产生力，肥胖和全身性血糖，从而揭示了一种新颖骨骼肌生理学中Swell1-Akt-MTOR信号轴的作用。此外，我们的小组现在有已发表和未发表的生化，斑块钳和成像证据表明Swell1通道复合物也表达并在溶酶体（Lyso-Swell1）中起作用 - 也支持一个概念通过最近无偏见的CRISPR屏幕。鉴于溶酶体是整合营养感官的信号枢纽和Akt-MTOR信号传导，我们假设Swell1-LRC8通道共同调节质膜 PI3K-AKT信号传导和溶酶体中心营养-MTOR信号传导。为了检验这一假设，我们结合了我们在Swell1信号传导方面具有独特的试剂和专业知识，该试剂与Diwan（溶酶体信号传导），XU （溶酶体补丁钳）和迈耶（骨骼肌生理）实验室。我们的目标是了解质膜swell1信号传导和溶酶体Swell1（lyso-swell1）营养素的双重机制感测骨骼肌及其对骨骼肌生长和功能的贡献。这些理由研究是描述骨骼肌swell1-akt-mtor信号的分子机制将促进我们对新颖的，基本机制信号和营养感应机制的理解调节骨骼肌的生长和功能。我们提出以下目标： ·目标＃1：描述质膜与溶酶体swell1信号传导的机制骨骼肌细胞中的MTOR信号传导。这些研究将测试用于细胞营养感应的新型范式通过体外的溶酶体离子通道信号传导复合物，为体内实验奠定了基础。 AIM＃2：检查Swell1信号传导对有氧肌肉，骨骼肌肉生长和通过训练和衰老进行体内产生。这些研究将定义Swell1的贡献向骨骼肌生长和体内信号传导发出信号，并随着老化的身份传导。