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

• 批准号: 10454421
• 负责人: Rajan Sah
• 金额: $ 43.78万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10454421
• 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

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 除了促进老龄化人口的整体健康之外，还包括糖尿病和心脏病等疾病。骨骼 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、代谢健康状况不佳以及死亡率增加。因此， 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 SWELL1-AKT-mTOR 信号轴在骨骼肌生理学中的作用。另外，我们组现在有 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 通过最近的无偏见 CRISPR 筛选。鉴于溶酶体是整合营养传感的信号中心 和 AKT-mTOR 信号传导，我们假设 SWELL1-LRRC8 通道共同调节质膜 PI3K-AKT 信号传导和以溶酶体为中心的营养物-mTOR 信号传导。为了检验这个假设，我们结合 我们在 SWELL1 信号传导方面独特的试剂和专业知识与 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) 营养物质的双重机制 骨骼肌的传感及其对骨骼肌生长和功能的贡献。这些的理由 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 增进我们对新颖、基本的机械信号和营养传感机制的理解 调节骨骼肌的生长和功能。我们提出以下目标： · AIM#1：描述质膜与溶酶体 SWELL1 信号传导至 AKT 的机制 骨骼肌细胞中的 mTOR 信号传导。这些研究将测试细胞营养传感的新范例 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 通过训练和衰老体内产生力量。这些研究将定义 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中的信号传导。