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.

项目概要众所周知，维持肌肉质量有助于预防肥胖和肥胖相关疾病例如糖尿病和心脏病，以及促进老龄化人口的整体健康。肌肉萎缩与癌症（恶病质）、心力衰竭、长期使用皮质类固醇、瘫痪或失神经（废用性萎缩）、衰老，导致代谢健康状况不佳，并增加死亡率。更深入地了解调节骨骼肌维持、生长和发育的分子机制功能对人类健康至关重要。我们最近表明，在骨骼肌中，SWELL1 是维持 AKT-mTOR 信号传导所必需的，正常情况下肌纤维大小、运动能力、力量产生、肥胖和全身血糖，从而揭示了一种新的此外，我们的团队现在已经了解了 SWELL1-AKT-mTOR 信号轴在骨骼肌生理学中的作用。已发表和未发表的生化、膜片钳和成像证据表明 SWELL1 通道复合物也在溶酶体中表达并发挥功能（Lyso-SWELL1）——这一概念也得到支持鉴于溶酶体是整合营养传感的信号中心，最近进行了一项公正的 CRISPR 筛选。和 AKT-mTOR 信号传导，我们探索了 SWELL1-LRRC8 通道共同调节质膜为了检验这一假设，我们将 PI3K-AKT 信号传导和以溶酶体为中心的营养物-mTOR 信号传导结合起来。我们在 SWELL1 信号传导方面的独特试剂和专业知识与 Diwan（溶酶体信号传导）Xu 的试剂和专业知识（溶酶体膜片钳）和迈耶（骨骼肌生理学）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) 营养物的双重机制骨骼肌的传感及其对骨骼肌生长和功能的贡献。研究表明，描绘骨骼肌 SWELL1-AKT-mTOR 信号传导的分子机制将有助于我们对新颖、基本的先进机械信号和营养传感机制的理解调节骨骼肌生长和功能。我们提出以下目标： · AIM#1：描述质膜与溶酶体 SWELL1 信号传递至 AKT 的机制这些研究将测试骨骼肌细胞中的 mTOR 信号传导的新范例。通过体外溶酶体离子通道信号复合物，为体内实验奠定了基础。 · AIM#2：检查 SWELL1 信号对有氧能力、骨骼肌生长和这些研究将确定 SWELL1 的贡献。骨骼肌生长的信号传导和体内信号传导以及衰老过程。