Fibro-adipogenic remodeling of the diaphragm in obesity-associated respiratory dysfunction

肥胖相关呼吸功能障碍中隔膜的纤维脂肪形成重塑

基本信息

批准号：
10594042
负责人：
ERIC D BURAS
金额：
$ 16.96万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10594042
关键词：
Abdomen Ablation Adipocytes Adipose tissue American Anatomy Animal Feed Animals Atrophic Autopsy Biological Models Biomechanics Body mass index Cardiac Cardiovascular system Cells Chest Clinical Clinical Research Collagen Data Defect Deposition Diagnosis Diphtheria Toxin Dyspnea Evaluation Event Exertion Experimental Models Failure Fibroblasts Fibrosis Functional disorder Gene Expression Profiling Generations High Fat Diet Histology Human Hypercapnia Impairment Individual Injury Intramuscular Isometric Contraction Isometric Exercise Learning Life Link Lung Measurement Measures Mechanics Mediating Mediator Mesenchymal Stem Cells Modeling Morbid Obesity Morbidity - disease rate Motion Mus Muscle Muscle Weakness Muscle function Obese Mice Obesity Overnutrition Pathologic Patients Phenotype Physiological Physiology Pickwickian Syndrome Polymers Proliferating Property Protocols documentation Respiration Disorders Respiratory Diaphragm Respiratory Muscles Sampling Skeletal Muscle Structure Structure-Activity Relationship Testing Thinness Time Tissue Expansion Tissue Sample Tissues Training Ultrasonography Visceral Weight Whole Body Plethysmography Work cardiovascular risk factor diet-induced obesity dietary control feeding high risk in vivo lipid biosynthesis mdx mouse mortality mouse model muscle regeneration muscular dystrophy mouse model novel obese patients prevent progenitor respiratory response stem cell population transcriptome transcriptome sequencing ultrasound ventilation

项目摘要

Abstract: Obesity-associated respiratory complications range from simple dyspnea on exertion to life-threatening obesity hypoventilation syndrome (OHS). The latter, defined by PaCO2 >45 torr in individuals with body mass index (BMI) >30kg/m2 and no alternative cause of hypercapnia, is associated with severe cardiac complications and increased mortality. While inability of the lungs to expand against abdominal and thoracic adipose tissue is thought to drive this ventilatory compromise, clinical studies have also identified respiratory muscle weakness in obese patients. Moreover, large adipocyte inclusions are seen in diaphragms of subjects with OHS but not in obese/normocapnic or lean individuals. These findings suggest the diaphragm itself may be compromised with obesity; however, impacts of over-nutrition on structure and function of this muscle are not well defined. In mice subjected to a long-term diet-induced obesity (DIO) time course, we observed hypercapnia after 6 months high fat diet (HFD) feeding. This temporally corresponded with impaired diaphragm muscle function—assessed in vivo by ultrasonography and ex vivo by measurement of contractile force. Adipose tissue expansion and collagen deposition within the diaphragm temporally corresponded with hypercapnia and quantitatively correlated with ex vivo contractile deficits. Lineage tracing showed all intra-diaphragmatic adipocytes and many collagen-producing cells to arise from fibro-adipogenic progenitors (FAPs), a skeletal muscle mesenchymal stem cell population. FAP number, proliferation, and collagen deposition increased with obesity. We hypothesize that FAP-mediated, fibro-adipogenic remodeling of the diaphragm impairs ventilatory function in obesity. In Aim 1, we will test whether obesity per se impairs ventilation and diaphragm function by analyzing weight-matched genetically obese and DIO mice. Ex vivo, we will measure contractile function and passive stiffness of large muscle isolates and individual myofibers to determine whether biomechanical defects occur at the tissue or cellular level. Finally, we will determine quantitative correlations of intra-diaphragmatic adipocyte number and polymerized collagen with these physiologic parameters. In Aim 2, we specifically test the hypothesis that FAPs mediate diaphragm fibro-adipogenic remodeling and dysfunction in obesity. We will analyze FAP response to obesity with global gene expression profiling and ex vivo proliferation, adipogenesis and collagen deposition quantification. We will then determine whether (diphtheria toxin-mediated) FAP ablation prevents diaphragm fibro-adipogenic changes and dysfunction in a DIO model. In Aim 3, we will analyze tissue samples and FAPs isolated from human autopsy samples to determine whether similar changes occur in obese humans and associate with clinical OHS diagnosis. The work will define a cellular mechanism of OHS; and completion of the project will provide training in muscle biomechanics, RNA-Seq and human sample analysis.

抽象的：与肥胖相关的呼吸系统并发症包括从简单的劳力性呼吸困难到危及生命的肥胖通气不足综合征 (OHS)，定义为体重指数个体的 PaCO2 >45 托。 (BMI) >30kg/m2 并且没有其他原因导致高碳酸血症，与严重的心脏并发症和死亡率增加，而肺部无法扩张腹部和胸部脂肪组织。临床研究还发现，呼吸肌无力是导致这种通气损害的原因此外，肥胖患者的膈肌中可见到大的脂肪细胞内含物，但在 OHS 受试者中则没有。肥胖/血二氧化碳正常或瘦的个体。这些发现表明膈肌本身可能受到损害。肥胖；然而，营养过剩对小鼠肌肉结构和功能的影响尚不清楚。经过长期饮食诱导肥胖 (DIO) 时间过程，我们在 6 个月的高碳酸血症后观察到高碳酸血症脂肪饮食（HFD）喂养在时间上与膈肌功能受损相对应——在体内超声检查和体外脂肪组织扩张和胶原蛋白测量。隔膜内的沉积在时间上与高碳酸血症相对应，并与 ex 定量相关体内收缩缺陷。谱系追踪显示所有膈内脂肪细胞和许多胶原蛋白生成细胞。细胞来自纤维脂肪祖细胞（FAP），一种骨骼肌间充质干细胞群。 FAP 数量、增殖和胶原沉积随着肥胖而增加。我们研究发现 FAP 介导的膈肌纤维脂肪重塑会损害通气功能在目标 1 中，我们将通过以下方式测试肥胖本身是否会损害通气和膈肌功能。通过离体分析体重匹配的遗传肥胖小鼠和 DIO 小鼠，我们将测量收缩功能和大肌肉分离物和单个肌纤维的被动刚度以确定是否存在生物力学缺陷最后，我们将确定膈内的定量相关性。在目标 2 中，我们专门测试了脂肪细胞数量和聚合胶原蛋白与这些生理参数。 FAP 介导肥胖症中隔膜纤维脂肪形成重塑和功能障碍的假设。通过全局基因表达谱和离体增殖、脂肪生成来分析 FAP 对肥胖的反应然后我们将确定是否（白喉毒素介导的）FAP 消融。防止 DIO 模型中膈肌纤维脂肪形成的变化和功能障碍。在目标 3 中，我们将分析组织。从人体尸检样本中分离出的样本和 FAP，以确定肥胖者是否会发生类似的变化人类并与临床 OHS 诊断相关联，这项工作将定义 OHS 的细胞机制；该项目完成后将提供肌肉生物力学、RNA-Seq 和人体样本分析方面的培训。