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

基本信息

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
项目类别：
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

项目摘要

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）：该提案的目标是开发和表征一种新型小鼠品系，该品系将允许对成体骨骼肌中的卫星细胞进行有条件的遗传标记。卫星细胞是成体骨骼肌的生肌干细胞，在出生后生长和受伤后的肌肉再生过程中得到最多的研究。除了推测之外，由于难以准确识别卫星细胞并且无法随着时间的推移稳定地跟踪它们的频率和行为，卫星细胞在整个生命过程中维持骨骼肌的作用尚未得到直接研究。为了克服这一障碍，在目标 1 中，我们将通过将条件卫星细胞特异性驱动/诱导小鼠系 (Pax7-CreER) 与核定位 GFP-lacZ 报告小鼠系 (Rosa26-GNZ) 杂交来生成 Pax7-GNZ 小鼠。）。该提案的一个主要优点是生成 Pax7-GNZ 系所需的亲本菌株已经存在。 Pax7-GNZ 小鼠系的表征需要量化报告基因有效标记卫星细胞的特异性和程度。然后，通过在 3 个月大的小鼠中诱导报告基因表达来确定卫星细胞在维持肌肉质量中的作用，并在小鼠整个生命周期的后期时间点进行分析。目标 2 将开始确定卫星细胞对衰老肌肉适应需求变化的能力受损的影响。 Pax7-GNZ 小鼠将用于量化卫星细胞动力学，其中增效剂消融诱导的肌肉肥大以及后肢卸载诱导的肌肉萎缩后的重新生长。 Pax7-GNZ 小鼠品系代表了一种强大、独特的遗传工具，它将首次对正常肌肉老化期间以及需求变化期间维持肌肉的卫星细胞动态进行全面而准确的量化，例如肥大和萎缩后质量的恢复。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专门消融成年骨骼肌中卫星细胞对肌肉可塑性的影响。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，以及它如何随年龄变化。公共卫生相关性：近三分之一的老年人患有虚弱的疾病。老年衰弱的原因尚不清楚，但一个促成因素是肌肉减少症，即肌肉质量随着年龄的增长而逐渐丧失。卫星细胞（成人骨骼肌的主要干细胞）的缺陷被认为起着核心作用。该提案的目标是开发和表征一种新型小鼠模型，以跟踪衰老骨骼肌中的卫星细胞，以更好地了解它们在肌肉减少症中的作用。该研究项目的长期目标是开发一种治疗干预措施来预防肌肉减少症并减少老年人衰弱的发生率。