Skeletal Muscle Loss and Dysfunction

骨骼肌损失和功能障碍

基本信息

批准号：
10561633
负责人：
Nathan K LeBrasseur
金额：
$ 50.83万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10561633
关键词：
Adipocytes Age Aging Anabolic Agents Apoptosis Apoptotic Applications Grants Atrophic Biology CDKN2A gene Cell Aging Cells Coculture Techniques Cre-LoxP Cyclin-Dependent Kinase Inhibitor Cytometry Data Detection Deterioration Disease Drug Screening Elderly Endothelium Fatty acid glycerol esters Fiber Fibroblasts Fibrosis Foundations Functional disorder Genetic Geroscience Goals Health Histologic Histology Human Immune Impairment In Vitro Infiltration Inflammation Influenza Intuition Maps Measures Mediator Metabolic Mus Muscle Muscle Cells Myoblasts Natural regeneration Pathology Performance Pharmaceutical Preparations Phenotype Physical Function Physically Challenged Population Program Research Project Grants Proliferating Proteins Resistance Resources Role Science Skeletal Muscle Stress Testing Therapeutic Tissues Transgenes Transgenic Organisms Translations Transplantation Work age related aged bone health cardiovascular health cell type cellular targeting chemotherapy clinical application clinically relevant drug development drug discovery evidence base exercise intervention healthspan high dimensionality improved interdisciplinary approach molecular phenotype multidisciplinary muscle aging muscle form muscle strength new therapeutic target novel pharmacologic pre-clinical prevent progenitor programs promote resilience resilience response secondary analysis senescence skeletal muscle wasting tool translational potential

项目摘要

PROJECT 4: Skeletal Muscle Loss and Dysfunction – SUMMARY LeBrasseur In line with the overall goal of the Program Project Grant, Project 4 will test the central hypothesis that senescent cells mechanistically contribute to skeletal muscle aging and represent a novel druggable target to restore muscle performance, physical function, and organismal resilience. Our hypothesis is founded on our recent work demonstrating the role of cellular senescence, a hallmark of aging, in the genesis of multiple age- related conditions. Our preliminary data demonstrate expression of the cyclin-dependent kinase inhibitor p21Cip1, a marker and mediator of senescence, increases in aged murine and human skeletal muscle and negatively associates with measures of physical function. We show that p21Cip1, senescence-associated secretory phenotype (SASP), and anti-apoptotic proteins markedly increase in cultured myoblasts in response to senescence-inducing stress. Aged muscle is compositionally heterogenous, however, and senescence of other resident cell populations, including fibroadipogenic progenitor, endothelial, and immune cells, may also contribute to its degeneration. Consequently, there is a critical need to identify and comprehensively phenotype the cell populations within aged muscle that senesce and mechanistically contribute to its loss and dysfunction. To this end, in Aim 1 we will use mice harboring a transgene that enables the isolation of p21Cip1-expressing cells to quantify markers of senescence, the SASP, and anti-apoptosis pathways in muscle-resident cells of young and aged mice. High dimensional mapping of non-senescent and senescent cell populations will be accomplished through mass cytometry and advanced histological approaches. Aim 2, will directly compare the effects of genetic clearance of p21Cip-expressing cells to clearance of p16Ink4a-expressing cells on muscle health (e.g., mass, fibrosis, and fat infiltration) and measures of physical function and resilience with the support of Integrated Healthspan Phenotyping Core. We will also assess the relative efficacy of clearing specific p21Cip1-cell populations using novel Cre-LoxP lines and pharmacological agents developed and screened by the Drug Discovery and Development Core. Finally, Aim 3 will test the hypothesis that genetic and pharmacological clearance of senescent cells will potentiate the effects of a muscle building drug on measures of muscle health, physical function, and resilience. Secondary analyses will include the effects on metabolic, bone, and cardiovascular health in partnership with Projects 1, 2, and 3, respectively. Through the use of novel analytical, transgenic, and pharmacological tools and a multidisciplinary approach, we expect to advance our understanding of the fundamental biology of skeletal muscle aging. The application of clinically-relevant measures of physical function and resilience and evidence-based senotherapeutic compounds will facilitate the translation of preclinical discoveries to clinical application.

项目 4：骨骼肌损失和功能障碍 – 摘要 LeBrasseur 根据计划项目拨款的总体目标，项目 4 将检验以下中心假设：衰老细胞机械地导致骨骼肌衰老，并代表了一种新的药物靶标恢复肌肉性能、身体功能和生物弹性我们的假设是建立在我们的假设之上的。最近的工作证明了细胞衰老（衰老的标志）在多种年龄的发生中的作用我们的初步数据证明了细胞周期蛋白依赖性激酶抑制剂的表达。 p21Cip1 是衰老的标志物和介质，会增加老年小鼠和人类骨骼肌的数量，我们发现 p21Cip1 与衰老相关。分泌表型（SASP）和抗凋亡标记蛋白在培养的成肌细胞中增加然而，衰老的肌肉在成分上是异质的，并且衰老的压力。其他常驻细胞群，包括纤维脂肪祖细胞、内皮细胞和免疫细胞，也可能有助于其退化，因此迫切需要识别和全面的表型。衰老肌肉内的细胞群会衰老并机械地导致其丧失和功能障碍。为此，在目标 1 中，我们将使用携带转基因的小鼠，该转基因能够分离表达 p21Cip1 的细胞来量化衰老标记物、SASP 和肌肉驻留细胞中的抗凋亡途径年轻和老年小鼠的非衰老和衰老细胞群的高维绘图将是通过质谱流式细胞术和先进的组织学方法完成的目标 2，将直接比较 p21Cip 表达细胞的基因清除对肌肉上 p16Ink4a 表达细胞的清除的影响健康状况（例如，质量、纤维化和脂肪浸润）以及身体功能和恢复力的测量综合 Healthspan 表型核心的支持我们还将评估清除的相对功效。使用新型 Cre-LoxP 系和药物制剂开发和开发特定的 p21Cip1 细胞群最后，目标 3 将检验遗传和开发的假设。衰老细胞的药理清除将增强增肌药物对措施的影响肌肉健康、身体功能和恢复力的二次分析将包括对代谢的影响，分别与项目 1、2 和 3 合作通过使用新颖的药物来促进骨骼和心血管健康。分析、转基因和药理学工具以及多学科方法，我们期望推进我们的研究了解骨骼肌衰老的基本生物学及其临床相关的应用。身体机能和恢复力的测量以及基于证据的治疗化合物将促进将临床前发现转化为临床应用。