Effect of Satellite Cell Ablation on the Aging Diaphragm

卫星细胞烧蚀对老化隔膜的影响

• 批准号: 8638431
• 负责人: Esther E Dupont-Versteegden
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638431
• 关键词: A Mouse; Ablation; Age; Age-Months; Aging; Area; Behavior; Breathing; Coughing; Data; Diphtheria Toxin; Elderly; Environmental air flow; Exercise; Extracellular Matrix Protein Gene; Fibrosis; Functional disorder; Genetic Models; Health; Health Care Costs; Hypoxia; Impairment; In Vitro; Institutionalization; Intervention; Knowledge; Lead; Life; Limb structure; Maintenance; Measures; Mediating; Modeling; Motor; Mus; Muscle; Muscle Fibers; Muscle function; Muscle satellite cell; Muscular Atrophy; Pathology; Play; Positioning Attribute; Process; Protein Biosynthesis; Quality of life; Reflex action; Respiratory Diaphragm; Respiratory Muscles; Respiratory physiology; Role; Running; Skeletal Muscle; Sneezing; Structure; Tamoxifen; Testing; Time; Voice; Work of Breathing; Workload; age related; aged; combat; effective intervention; frailty; in vivo; insight; mdx mouse; muscle aging; muscular structure; protein degradation; public health relevance; respiratory; response; satellite cell; skeletal muscle wasting; stem; therapy design

Motor dysfunction and skeletal muscle wasting are major causes of poor quality of life, increased health care costs, and institutionalization in the elderly. However, age-related dysfunction of the respiratory muscles has an even greater impact on quality of life: impairment of the aging diaphragm disrupts a number of important behaviors, such as breathing, airway protective reflexes (coughing and sneezing), and voice. Since the diaphragm and accessory respiratory muscles must be active throughout life to sustain ventilation, it is not surprising that their response to aging diverges from that seen in other skeletal muscles. In contrast to limb muscles, atrophy does not explain the weakness and increased fatigability of the aging diaphragm; however, since the diaphragm is constantly active it may have a need for constant remodeling. Indirect evidence for this notion stems from the fact that there is an apparent depletion of satellite cells in diaphragm muscle of mdx mice, rendering it more susceptible to damage. Whether a similar situation exists for aging diaphragm muscle and whether satellite cell depletion and/or dysfunction play a role in decreased diaphragm function with age are completely unexplored issues. We are in the unique position to test the role of satellite cells in diaphragm muscle with aging using the Pax7-DTA mouse, which allows for temporal and specific control of satellite cell ablation; we showed previously that >90% of satellite cells are ablated in response to tamoxifen treatment using this genetic model. It is currently unknown what the role of satellite cells is in the maintenance of diaphragm function with aging by itself, or when the muscle is functionally challenged. Therefore our hypothesis is that satellite cells are necessary to sustain the structure and function of the aging diaphragm, allowing it to withstand functional challenges. We will test the hypothesis using two specific aims. In Aim 1 we will determine whether satellite cell ablation in Pax7-DTA mice alters structure and function of the diaphragm with aging. Satellite cells will be ablated at 4 months of age and mice will be tested at 6, 18, and 24 months of age. The efficiency of satellite cell ablation will be measured, and analyses will be performed to assess morphological as well as functional changes in the diaphragm, and in ventilation in vivo. In Aim 2 we will establish whether satellite cell ablation impairs the ability of the aging diaphragm to adapt to functional challenges. Satellite cells will be ablated at 4 months of age and mice will be subjected to normobaric hypoxia for 4 weeks or running activity for 8 weeks. Analyses will be performed as in Aim 1 and compared to measures obtained from mice in Aim 1. We expect that satellite cell ablation causes detrimental functional and structural changes in the aged diaphragm, and that the ability of the diaphragm to adapt to changes in functional demand is impaired, particularly in the aged. With the studies proposed in this application, we will provide insight into the role of satellite cells in diaphragm muscle with advancing age, which is an unexplored area; this knowledge will enable us to develop effective intervention strategies for the loss of diaphragm function with age.

运动功能障碍和骨骼肌浪费是生活质量差的主要原因，医疗保健增加 老年人的成本和制度化。但是，呼吸肌的年龄相关功能障碍具有 对生活质量的影响更大：衰老diaphragm的损害破坏了许多重要的 行为，例如呼吸，气道保护反射（咳嗽和打喷嚏）和声音。自从 隔膜和配件呼吸道肌肉必须在一生中活跃以维持通风，不是 令人惊讶的是，他们对衰老的反应与其他骨骼肌中看到的反应不同。与肢体相反 肌肉，萎缩不能解释衰老隔膜的弱点和疲劳性。然而， 由于隔膜不断活跃，因此可能需要恒定重塑。间接证据 概念源于以下事实：MDX的隔膜肌肉中卫星细胞明显耗尽 小鼠，使其更容易受到损害。衰老的肌肉是否存在类似情况 以及卫星细胞的耗竭和/或功能障碍是否在年龄降低的隔膜功能中起作用 是完全未开发的问题。我们处于独特的位置，可以测试卫星细胞在隔膜中的作用 使用PAX7-DTA小鼠衰老的肌肉，该小鼠允许对卫星细胞的时间和特定控制 消融;我们以前表明，> 90％的卫星细胞响应着他莫昔芬治疗而消融 使用这种遗传模型。目前尚不清楚卫星细胞在维护中的作用 隔膜功能与衰老本身或肌肉在功能挑战时。因此我们的 假设是卫星细胞是维持老化隔膜的结构和功能所必需的， 允许它承受功能挑战。我们将使用两个具体目标检验假设。在目标1中我们 将确定PAX7-DTA小鼠中的卫星细胞消融是否改变了diaphragm的结构和功能 随着衰老。卫星细胞将在4个月大时消融，将在6、18和24个月进行测试 年龄。将测量卫星细胞消融的效率，并将进行分析以评估 隔膜的形态和功能变化以及体内通风。在目标2中，我们将 确定卫星细胞消融是否会损害衰老隔膜适应功能的能力 挑战。卫星细胞将在4个月大时消融，小鼠将受到正常的缺氧。 进行4周或跑步活动8周。分析将如AIM 1中进行，并与措施进行比较 从AIM 1中获得的小鼠获得。我们期望卫星细胞消融会导致有害的功能和结构 老年隔膜的变化，以及隔膜适应功能需求变化的能力 受损，尤其是在老年人中。随着本应用程序提出的研究，我们将洞悉 卫星细胞在隔膜肌肉中的作用随着年龄的增长，这是一个未开发的区域。这个知识 将使我们能够制定有效的干预策略，以使隔膜功能随着年龄的增长而丧失。