Defining the role of satellite cells in muscle maintenance throughout the lifespa

定义卫星细胞在整个生命周期肌肉维持中的作用

• 批准号: 7907774
• 负责人: CHARLOTTE A. PETERSON
• 金额: $ 25.73万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907774
• 关键词: Ablation; Adult; Age; Aging; Apoptosis; Atrophic; Behavior; Cell Count; Data; Defect; Elderly; Foundations; Frequencies; Future; Gene Expression; Genetic; Goals; Growth; Hindlimb Suspension; Homeostasis; Hypertrophy; Incidence; Injury; Label; LacZ Genes; Life; Longevity; Maintenance; Modeling; Mus; Muscle; Muscular Atrophy; Nuclear; Phenotype; Play; Reporter; Reporter Genes; Research Project Grants; Role; Skeletal Muscle; Skeletal Muscle Satellite Cells; Specificity; Therapeutic Intervention; Time; Validation; adult stem cell; frailty; migration; mouse model; muscle aging; muscle form; muscle hypertrophy; muscle regeneration; novel; prevent; public health relevance; restoration; sarcopenia; satellite cell; skeletal muscle plasticity; tool; Ablation; Adult; Age; Aging; Apoptosis; Atrophic; Behavior; Cell Count; Data; Defect; Elderly; Foundations; Frequencies; Future; Gene Expression; Genetic; Goals; Growth; Hindlimb Suspension; Homeostasis; Hypertrophy; Incidence; Injury; Label; LacZ Genes; Life; Longevity; Maintenance; Modeling; Mus; Muscle; Muscular Atrophy; Nuclear; Phenotype; Play; Reporter; Reporter Genes; Research Project Grants; Role; Skeletal Muscle; Skeletal Muscle Satellite Cells; Specificity; Therapeutic Intervention; Time; Validation; adult stem cell; frailty; migration; mouse model; muscle aging; muscle form; muscle hypertrophy; muscle regeneration; novel; prevent; public health relevance; restoration; sarcopenia; satellite cell; skeletal muscle plasticity; tool

DESCRIPTION (provided by applicant): The goal of this proposal is to develop and characterize a novel mouse line which will allow for the conditional, genetic labeling of satellite cells in adult skeletal muscle. Satellite cells are the myogenic stem cell of adult skeletal muscle and have been most studied during post-natal growth and during muscle regeneration following injury. Beyond speculation, the role of satellite cells in the maintenance of skeletal muscle throughout life has yet to be directly studied due to the difficulty of accurately identifying satellite cells and the inability to stably track their frequency and behavior over time. To overcome this obstacle, in Aim 1 we will generate the Pax7-GNZ mouse by crossing the conditional, satellite cell-specific driver/inducer mouse line (Pax7-CreER) with a nuclear-localized GFP-lacZ reporter mouse line (Rosa26-GNZ). A major strength of the proposal is that the parental strains required to generate the Pax7-GNZ line already exist. Characterization of the Pax7-GNZ mouse line will entail quantifying the specificity and magnitude to which the reporter gene effectively marks satellite cells. The role of satellite cells in maintaining muscle mass will then be determined by inducing reporter gene expression in 3 month old mice which will be analyzed at later time points throughout the lifespan of the mice. Aim 2 will begin to determine the contribution of satellite cells to the compromised ability of aging muscle to adapt to changes in demand. The Pax7-GNZ mice will be used to quantify satellite cell dynamics with muscle hypertrophy induced by synergist ablation and re-growth following muscle atrophy induced by hindlimb unloading. The Pax7-GNZ mouse line represents a powerful, unique genetic tool that will allow for the first time, a comprehensive and accurate quantification of satellite cell dynamics in the maintenance of muscle during normal muscle aging, as well as during periods of altered demand such as hypertrophy and restoration of mass following atrophy. Furthermore, results obtained will serve as the foundation for future studies using a genetic mouse model to examine the impact on muscle plasticity of specifically ablating satellite cells in adult skeletal muscle. These studies will define the function of satellite cells in skeletal muscle plasticity and homeostasis and how it may change with age. PUBLIC HEALTH RELEVANCE: Almost one-third of the elderly suffer from the debilitating condition of frailty. The cause of geriatric frailty is not known but a contributing factor is sarcopenia, the progressive loss of muscle mass with age. Defects in satellite cells, the primary stem cell of adult skeletal muscle, are thought to play a central role. The goal of this proposal is to develop and characterize a novel mouse model to track satellite cells in aging skeletal muscle with the aim to better understand their role in sarcopenia. The long-term goal of the research project is to develop a therapeutic intervention to prevent sarcopenia and reduce the incidence of frailty in the elderly.

描述（由申请人提供）：该提案的目的是开发和表征一条新型的小鼠系，这将允许成人骨骼肌中卫星细胞的条件遗传标记。卫星细胞是成年骨骼肌的肌源性干细胞，在产后生长和受伤后肌肉再生期间对卫星细胞进行了最多的研究。除了猜测之外，由于难以准确识别卫星细胞的困难以及无法稳定跟踪其频率和行为，卫星细胞在一生中维持骨骼肌中的作用尚未直接研究。为了克服这一障碍，在AIM 1中，我们将通过越过条件的，卫星细胞特异性驱动器/诱导型小鼠系（PAX7-CREER）来生成PAX7-GNZ小鼠，并使用核位置的GFP-LACZ RACZ REPORTER小鼠系（RosA26-GNZ）生成PAX7-GNZ小鼠。该提案的一个主要优势是生成PAX7-GNZ线所需的父母菌株已经存在。 PAX7-GNZ小鼠系的表征将需要量化报告基因有效标记卫星细胞的特异性和幅度。然后，卫星细胞在维持肌肉质量中的作用将通过诱导3个月大的小鼠中的报告基因表达来确定，该基因表达将在小鼠的整个寿命中进行以后的时间点进行分析。 AIM 2将开始确定卫星细胞对衰老肌肉适应需求变化的能力的贡献。 PAX7-GNZ小鼠将用于量化卫星细胞动力学用肌肉肥大，由协同消融诱导并在后肢卸载引起的肌肉萎缩后诱导的肌肉肥大。 PAX7-GNZ小鼠线代表了一种强大的独特遗传工具，该工具将首次允许，在正常的肌肉衰老期间以及需求变化时期（如肥大和肿瘤后质量恢复），对卫星细胞动力学进行了全面，准确的量化卫星细胞动力学。此外，获得的结果将作为未来研究的基础，使用遗传小鼠模型来检查成人骨骼肌中特定消融卫星细胞的肌肉可塑性的影响。这些研究将定义卫星细胞在骨骼肌可塑性和稳态中的功能，以及它如何随着年龄的变化而变化。 公共卫生相关性：几乎三分之一的老人遭受了脆弱状况的衰弱状况。老年脆弱的原因尚不清楚，但促成因素是肌肉减少症，这是随着年龄的增长而进行的肌肉质量的逐渐丧失。卫星细胞中的缺陷是成年骨骼肌的主要干细胞，被认为起着核心作用。该建议的目的是开发和表征一种新型的小鼠模型，以跟踪骨骼肌衰老的卫星细胞，以便更好地了解其在肌肉减少症中的作用。研究项目的长期目标是开发一种治疗性干预措施，以防止肌肉减少症并减少老年人的脆弱性。