The effects of exercise on satellite cell dynamics during aging

运动对衰老过程中卫星细胞动态的影响

基本信息

批准号：
9026853
负责人：
JOHN Joseph MCCARTHY
金额：
$ 32.72万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9026853
关键词：
Ablation Address Adult Affect Age Age-Months Aging Biological Assay Breeding CD34 gene Cell Nucleus Cell physiology Cells Coculture Techniques Collagen Data Development Disease Elderly Environment Etiology Exercise Fiber Fibroblasts Fibrosis Functional disorder Gastrocnemius Muscle Gene Targeting Genetic Goals Growth Homeostasis Human Hypertrophy Immunohistochemistry Individual Integrins Intervention Knock-out Knowledge Label Life Longevity MAPK14 gene Maintenance Measures Mediating Methods MicroRNAs Modeling Molecular Profiling Mouse Strains Mus Muscle Muscle Fibers Nucleosomes Outcome Phase Phenotype Physical activity Production Proteins Publishing Quality of life Regulation Reporter Reporting Research Rodent Role Running Skeletal Muscle Skeletal Muscle Satellite Cells Stem cells Stimulus Testing Therapeutic Time Untranslated Regions Work abstracting base exosome extracellular falls frailty improved loss of function muscle aging muscle form muscle hypertrophy muscle strength normal aging novel progenitor regenerative research study response sarcopenia satellite cell sedentary senescence skeletal skeletal muscle growth tool

项目摘要

Abstract A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength. Although the etiology of sarcopenia remains to be determined, studies in humans and rodents have reported a strong correlation between the loss and/or dysfunction of satellite cells and sarcopenia. Despite the correlation between declining satellite cell-dependent regenerative capacity and age, no studies to date have directly tested this relationship to determine if the loss of satellite cells causes sarcopenia. To test this idea, we depleted (>85%) satellite cells in five month old mice to a level dramatically lower than that observed with normal aging. A detailed analysis of multiple muscles through 24 months of age revealed that, despite significantly reduced regenerative capacity, the life-long depletion of satellite cells did not accelerate nor exacerbate sarcopenia; however, the depletion of satellite cells at a young age was associated with a significant increase in fibrosis in old mice. These highly provocative findings, together with our data on the fiber-type specific role of satellite cells in response to exercise, reveal our limited understanding of how aging affects the function of satellite cells in skeletal muscle maintenance, the development of fibrosis and in response to a growth stimulus; addressing these fundamental gaps in our knowledge clearly requires new tools. Towards this end, we will utilize a novel mouse strain (Pax7-H2B-GFP) that will allow us to track satellite cell dynamics for the first time in adult skeletal muscle aging. To better understand how aging and exercise affects satellite cell dynamics and the regulation of fibrosis, the following aims will be pursued: 1) determine how age and life-long exercise affects satellite cell dynamics in the maintenance of skeletal muscle, 2) determine how age and life-long exercise affects satellite cell regulation of fibrosis and 3) determine how age affects satellite cell dynamics in response to a growth stimulus. The approaches described herein use powerful, new genetic tools to determine how aging and life-long exercise alters the function of satellite cells in skeletal muscle homeostasis, regulation of fibrosis and adaptability. The development of the Pax7-H2B-GFP mouse represents a long sought-after method for tracking satellite cells, especially following fusion into the myofiber. This novel mouse strain will allow us to address formally intractable questions regarding how satellite cell dynamics are affected by age and life-long exercise. Such fundamental knowledge is necessary to critically evaluate the therapeutic value of satellite cells for the treatment of muscle mass loss and function associated with aging.

抽象的老年衰弱的一个关键决定因素是肌肉减少症，即与年龄相关的骨骼肌质量损失和力量。尽管肌肉减少症的病因仍有待确定，但对人类和啮齿动物的研究已经表明据报道，卫星细胞的丢失和/或功能障碍与肌肉减少症之间存在很强的相关性。尽管卫星细胞依赖性再生能力下降与年龄之间的相关性，迄今为止尚无研究表明直接测试这种关系以确定卫星细胞的丢失是否会导致肌肉减少症。为了测试这个想法，我们五个月大小鼠的卫星细胞被耗尽（>85%），其水平显着低于用正常老化。对 24 个月龄多块肌肉的详细分析表明，尽管再生能力显着降低，卫星细胞的终生损耗既没有加速也没有加剧肌肉减少症；然而，年轻时卫星细胞的耗尽与老年小鼠的纤维化显着增加。这些极具挑战性的发现，以及我们的数据纤维型卫星细胞在运动中的特定作用，揭示了我们对衰老如何发生的有限了解影响卫星细胞在骨骼肌维持、纤维化发展和对增长刺激的反应；解决我们知识中的这些根本差距显然需要新的工具。为此，我们将利用一种新型小鼠品系 (Pax7-H2B-GFP)，它将使我们能够跟踪卫星首次研究成人骨骼肌衰老的细胞动力学。为了更好地了解衰老和运动如何影响卫星细胞动力学和纤维化的调节，将追求以下目标：1）确定年龄和终生锻炼如何影响维持骨骼肌的卫星细胞动力学，2) 确定年龄和终生锻炼如何影响卫星细胞对纤维化的调节；3) 确定年龄如何影响卫星细胞对纤维化的调节影响卫星细胞响应生长刺激的动态。本文描述的方法使用强大的新型遗传工具可确定衰老和终生锻炼如何改变卫星细胞的功能骨骼肌稳态、纤维化调节和适应性。 Pax7-H2B-GFP的开发小鼠代表了一种长期追捧的跟踪卫星细胞的方法，特别是在融合到卫星细胞中之后肌纤维。这种新型小鼠品系将使我们能够解决有关卫星如何细胞动力学受到年龄和终生锻炼的影响。这些基础知识是批判性地必需的评估卫星细胞治疗肌肉质量损失和相关功能的治疗价值随着衰老。