Arginase 1 in age-dependent muscle and bone loss

精氨酸酶 1 在年龄依赖性肌肉和骨质流失中的作用

• 批准号: 10228818
• 负责人: Sadanand tukdoji Fulzele
• 金额: $ 38.45万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228818
• 关键词: ARG2 gene; Address; Advanced Development; Affect; Age; Aging; Anabolism; Arginine; Atrophic; Biological Availability; Bone Marrow; Bone Tissue; Catabolism; Cell Aging; Cell Differentiation process; Cell Survival; Cells; Citrulline; DYSF gene; Data; Enzymes; Event; Financial Hardship; Follistatin; Fracture; Functional disorder; GDF8 gene; Genes; Goals; Homeostasis; Human; Impairment; Incidence; Knockout Mice; Lead; Mammalian Cell; Membrane Proteins; Metabolism; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle satellite cell; Muscular Atrophy; Musculoskeletal; Myoblasts; Nitric Oxide; Nitric Oxide Synthase; Ornithine; Osteoblasts; Osteoporosis; Outcome; Outcome Study; Oxidants; Oxidative Stress; Peroxonitrite; Play; Prevention strategy; Production; Protein Isoforms; Publishing; Quality of life; Reactive Oxygen Species; Role; Stress; Stromal Cells; Superoxides; Testing; Translations; Urea; age related; age-related muscle loss; arginase; base; bone; bone cell; bone loss; bone quality; caveolin-3; disability; falls; functional outcomes; inhibitor/antagonist; muscle aging; novel therapeutics; osteogenic; overexpression; pre-clinical; premature; prevent; reduced muscle mass; repaired; sarcopenia; satellite cell; senescence; stem cells; urea cycle

Abstract Aging is associated with reduced muscle mass (sarcopenia) and poor bone quality (osteoporosis) which together increase the incidence of falls and bone fractures. It is widely appreciated that aging triggers systemic oxidative stress which can impair bone and muscle stem cell survival and differentiation; yet, the basic mechanisms underlying these age- associated degenerative changes are not well understood. Our preliminary studies demonstrate that (1) levels of reactive oxygen species (ROS) increase significantly in muscle and bone tissues with aging, 2) arginase inhibitor treatment prevents oxidative stress-dependent elevation of atrophy-associated myokines (e.g., myostatin), premature cell senescence and supports myotube formation, 3) arginase inhibition prevents loss of membrane proteins Caveolin 3 (CAV3) and Dysferlin (DYSF) in differentiating myotube, 4) arginase inhibition enhances the expression of osteogenic genes (RUNX2) in bone marrow stromal cells (BMSCs). Based on our new and published findings, our central hypothesis is that elevated levels of ARG1 in bone and muscle cells cause uncoupling of nitric oxide synthesis (NOS), reducing NO formation and further increasing the burden of ROS formation and resulting in imbalanced bone and muscle homeostasis. Furthermore, blocking ARG1 activity or expression can prevent or reduce bone and muscle loss. This hypothesis will be tested with three independent but related aims. Specific Aim 1: Test the hypothesis that inhibition of arginase or lack of expression in muscle and bone can effectively prevent or reduce age dependent muscle and bone loss. We will use muscle- and bone-specific (BMSCs, and osteoblast) ARG1 knockout mice to examine the role of ARG1 in age-dependent loss in musculoskeletal function. Specific Aim 2: Test the hypothesis that age-related increases in arginase activity directly impact key cellular events in muscle and bone anabolism and catabolism. We will use primary human and mouse myoblast and bone cells (BMSC) to test this hypothesis. Specific Aim 3: Determine the molecular mechanisms by which ARG1 modulates muscle and bone homeostasis. We will test the hypothesis that dysregulation of ARG1 affects (a) nitric oxide-follistatin axis in muscle, (b) affects muscle repair/remodeling by altering membrane proteins (CAV3, DYSF) expression in muscles and (c) nitric oxide-RUNX2 axis in bone progenitor cells. Our application will facilitate the successful preclinical translation of ARG1 inhibition as a novel therapeutic strategy for age- related muscle and bone loss.

抽象的 衰老与肌肉质量减少（肌肉减少症）和骨质差有关 （骨质疏松症），加上跌落和骨折的发生率。它是广泛的 人们认为，衰老会触发会损害骨骼和肌肉的全身氧化应激 干细胞存活和分化；然而，这些年龄的基本机制 - 相关的退行性变化尚不清楚。我们的初步研究表明 （1）肌肉和骨骼中活性氧（ROS）的水平显着增加 衰老的组织2）精氨酸酶抑制剂治疗可防止氧化应激依赖性升高 与萎缩相关的肌动物（例如，肌生抑素），过早的细胞衰老和支持 肌管形成，3）精氨酸酶抑制可防止膜蛋白卡韦洛尔3的损失 （Cav3）和Dysferlin（DYSF）在分化Myotube中，4）精氨酸酶抑制作用增强了 骨髓基质细胞（BMSC）中成骨基因（RUNX2）的表达。基于我们 新的和发表的发现，我们的中心假设是骨骼中的Arg1水平升高 肌肉细胞会导致一氧化氮合成（NOS）的解偶联，从而减少了不形成和 进一步增加ROS形成的负担，并导致骨骼和肌肉不平衡 稳态。此外，阻止ARG1活动或表达可以预防或减少骨骼 和肌肉损失。该假设将通过三个独立但相关的目标进行检验。 特定目的1：检验抑制精氨酸酶或缺乏表达的假设 肌肉和骨骼可以有效预防或减少依赖年龄的肌肉和骨质流失。我们 将使用肌肉和骨特异性（BMSC和成骨细胞）Arg1敲除小鼠检查 ARG1在年龄依赖性损失中的作用在肌肉骨骼功能中。特定目标2：测试 假设与年龄相关的精氨酸酶活性的增加直接影响关键细胞事件 肌肉和骨骼合物学和分解代谢。我们将使用原代人和老鼠成肌细胞 和骨细胞（BMSC）来检验该假设。特定目标3：确定分子 ARG1调节肌肉和骨稳态的机制。我们将测试 ARG1失调会影响（a）肌肉中的一氧化氮 - collistatin轴的假设，（b） 通过改变膜蛋白（CAV3，DYSF）的表达来影响肌肉修复/重塑 肌肉祖细胞中的肌肉和（C）一氧化氮runx2轴。我们的申请将有助于 ARG1抑制作用作为年龄的新型治疗策略的成功临床前翻译 相关的肌肉和骨质流失。