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Effect of Satellite Cell Ablation on the Aging Diaphragm

卫星细胞烧蚀对老化隔膜的影响

基本信息

批准号：
8741903
负责人：
Esther E Dupont-Versteegden
金额：
$ 18.75万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8741903
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

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：运动功能障碍和骨骼肌萎缩是老年人生活质量差、医疗保健费用增加和入院的主要原因。然而，与年龄相关的呼吸肌功能障碍对生活质量的影响更大：老化隔膜的损伤会扰乱许多重要的行为，例如呼吸、气道保护性反射（咳嗽和打喷嚏）和声音。由于膈肌和辅助呼吸肌必须在整个生命过程中保持活跃以维持通气，因此它们对衰老的反应与其他骨骼肌的反应不同也就不足为奇了。与四肢肌肉相反，萎缩并不能解释老化膈肌的无力和易疲劳性增加；然而，由于膈肌一直处于活动状态，因此可能需要不断重塑。这一观点的间接证据源于以下事实：mdx 小鼠的膈肌中卫星细胞明显减少，使其更容易受到损伤。衰老的膈肌是否存在类似的情况，以及卫星细胞耗竭和/或功能障碍是否在随年龄增长的膈肌功能下降中发挥作用，这些都是完全未经探索的问题。我们处于独特的地位，可以使用 Pax7-DTA 小鼠测试卫星细胞在膈肌中随衰老的作用，该小鼠可以对卫星细胞消融进行时间和特定的控制；我们之前表明，使用这种遗传模型，> 90% 的卫星细胞因他莫昔芬治疗而被消融。目前尚不清楚卫星细胞在维持隔膜功能随年龄增长或肌肉功能受到挑战时的作用。因此，我们的假设是卫星细胞对于维持老化隔膜的结构和功能是必要的，使其能够承受功能挑战。我们将使用两个具体目标来检验该假设。在目标 1 中，我们将确定 Pax7-DTA 小鼠的卫星细胞消融是否会随着衰老而改变膈肌的结构和功能。卫星细胞将在 4 个月大时被消融，小鼠将在 6、18 和 24 个月大时进行测试。将测量卫星细胞消融的效率，并进行分析以评估隔膜和体内通气的形态和功能变化。在目标 2 中，我们将确定卫星细胞消融是否会损害老化隔膜适应功能挑战的能力。卫星细胞将在 4 个月大时被消除，小鼠将接受 4 周的常压缺氧或 8 周的跑步活动。分析将按照目标 1 进行，并与目标 1 中从小鼠获得的测量结果进行比较。我们预计卫星细胞消融会导致老化隔膜发生有害的功能和结构变化，并且隔膜适应功能需求变化的能力受到损害，特别是在老年人中。通过本申请中提出的研究，我们将深入了解随着年龄的增长，卫星细胞在膈肌中的作用，这是一个尚未探索的领域；这些知识将使我们能够针对随年龄增长而丧失的膈肌功能制定有效的干预策略。