Skeletal Muscle Loss and Dysfunction

骨骼肌损失和功能障碍

• 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
• 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

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：骨骼肌肉损失和功能障碍 - 摘要勒布拉西尔 符合计划项目赠款的整体目标，项目4将测试中心假设 感觉细胞机械地有助于骨骼肌衰老，并代表了一个新的可吸毒目标 恢复肌肉性能，身体功能和有机弹性。我们的假设建立在我们的 最近的工作表明了细胞感应的作用，即衰老的标志，在多年龄的起源中 相关条件。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是一种感应的标记和介体，增加了老化的鼠和人骨骼肌，以及 与身体功能的测量负相关。我们表明P21CIP1，感应相关 秘书表型（SASP）和抗凋亡蛋白在培养的肌细胞中显着增加 引起感应应力。老年肌肉是完全异质的，但是 其他居民细胞种群，包括纤维脂肪生成祖细胞，内皮和免疫细胞，也可能 有助于其退化。因此，肯定需要识别和全面表型 传感器和机械造成其损失和功能障碍的老年肌肉中的细胞群体。 为此，在AIM 1中，我们将使用带有转换的小鼠，该转换能够隔离P21CIP1 细胞量化感应标记，SASP和抗凋亡途径 年轻的老鼠。非感官和感觉细胞种群的高维映射将是 AIM 2，将直接比较 p21CIP表达细胞的遗传清除对p16INK4A表达细胞清除肌肉的影响 健康（例如，质量，纤维化和脂肪浸润）以及对身体机能和韧性的测量 支持综合健康范围的表型核心。我们还将评估清除的相对效率 使用新型Cre-loxp系和药物的特定P21CIP1细胞种群开发了，并且 由药物发现和发育核心筛选。最后，AIM 3将检验遗传和遗传和 感觉细胞的药理清除率将潜在肌肉构建药物对测量的影响 肌肉健康，身体机能和韧性。次级分析将包括对代谢， 骨骼和心血管健康分别与项目1、2和3合作。通过使用小说 分析性，转基因和药品工具以及一种多学科的方法，我们希望推动我们的 了解骨骼肌衰老的基本生物学。与临床相关的应用 身体功能和弹性的度量以及基于证据的鼻疗法化合物将有助于 将临床前发现转换为临床应用。