Impact of Aging on Structure and Function of Pelvic Floor Muscles

衰老对盆底肌肉结构和功能的影响

基本信息

批准号：
9161987
负责人：
Marianna Alperin
金额：
$ 11.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2016-08-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9161987
关键词：
Accounting Affect Age Aging Architecture Area Atrophic Biochemical Cell Nucleus Cells Childbirth Collagen Data Defect Development Discipline Economic Burden Epidemiology Extracellular Matrix Failure Fatty acid glycerol esters Fecal Incontinence Female Fiber Fibrosis Functional disorder Glean Grant Human Image Immunohistochemistry Incidence Individual Infiltration Intramuscular Investigation Knowledge Lead Length Life Life Expectancy Limb structure Location Measures Mechanics Medicine Mental Depression Morbidity - disease rate Morphology Muscle Muscle Fibers Muscle function Muscle rehabilitation Muscle satellite cell Muscular Atrophy Myosin Heavy Chains Natural regeneration Operative Surgical Procedures Pathogenesis Pelvic Floor Disorders Pelvic Floor Muscle Pelvic floor structure Pelvis Personal Satisfaction Physiological Population Prevalence Prevention strategy Preventive Preventive Intervention Preventive measure Production Property Protein Isoforms Proxy Quality of life Rehabilitation therapy Research Resolution Risk Factors Sarcomeres Skeletal Muscle Social isolation Societies Specimen Staging Stem cells Structure Tensile Strength Testing Therapeutic Intervention Tissues Translations Urinary Incontinence Vagina Weight-Bearing state Woman age effect age related age-related muscle loss cost exhaustion functional decline healthy aging improved in vivo indexing innovation multidisciplinary muscle aging muscle form muscle regeneration muscle stiffness new therapeutic target novel older women pelvic organ prolapse regenerative sarcopenia satellite cell skeletal

项目摘要

PROJECT SUMMARY Aging is a key risk factor for pelvic floor disorders (PFDs), which include pelvic organ prolapse, and urinary and fecal incontinence. These common conditions interfere with the well-being of older women due to their negative impact on quality of life and associated morbidities.1 Prevalence of PFDs increase by 20% for each decade of life, reaching 50% in women age 80 and over.2 Importantly, as the U.S. population is aging, PFDs will affect an increasing proportion of women over the next decades, with a forecasted 44 million of women suffering from PFDs by 2050.2 Moreover, the substantial costs of PFDs will grow at twice the rate of the population due to the increased life expectancy in our society. Pelvic floor muscle (PFM) dysfunction is a critical defect in the progression to symptomatic PFDs.3,4 Despite this, the pathophysiology of PFDs and the cause of age-related PFM dysfunction remain poorly understood. As a result, there are currently no preventive measures and existing treatments are limited. In particular, PFM rehabilitation is less effective in older women, and surgical approaches are associated with high failure rates and adverse events.5,6 Consequently, many older women accept PFDs as an inevitable part of aging, when in fact they should demand more. It is well established that aging causes atrophy, fibrosis, and depletion of resident stem cells in limb and trunk muscles, resulting in age-related decline in muscle function.7,8,9 However, directly probing PFMs is not feasible due to their location deep within the pelvis. Current knowledge about PFMs is gleaned primarily from conventional radiological examinations that are compromised by low resolution and inability to distinguish between contractile and extracellular matrix components.10 As an alternative, human cadaveric specimens can be harnessed to begin to establish the mechanisms of age-related PFM dysfunction. The need to elucidate the pathogenesis of age-related PFDs and PFM dysfunction is clear: until basic mechanisms are established, treatments will offer marginal promise and preventive strategies will continue to be non-existent. We propose to determine functionally important age-related alterations, uncoupled from the consequences of childbirth, in the vital components of human PFMs (myofibers, extracellular matrix, stem cells). We will conduct direct examinations of cadaveric PFMs, obtained from younger and older female nulliparous donors. This project will test our overarching hypothesis that similar to other skeletal muscles, age- related atrophy, fibrosis, and diminished stem cell reservoir negatively impact PFM excursion, force production, mechanical properties, and regeneration. Our proposed cell and tissue level studies are enabled by a novel application of theoretical frameworks and advancements from other disciplines. These high-resolution analyses will facilitate the development of innovative and scientifically rationale preventive rehabilitation regiments and identification of novel therapeutic targets for mitigating age-related PFM dysfunction. Ultimately, we hope to reduce the burden of PFDs and improve the lives of millions of older women.

项目概要衰老是盆底疾病 (PFD) 的一个关键危险因素，其中包括盆腔器官脱垂和泌尿系统疾病。和大便失禁。这些常见状况会影响老年妇女的福祉，因为她们对生活质量和相关发病率产生负面影响。1 PFD 患病率每增加 20% 十年的寿命，在 80 岁及以上的女性中达到 50%。2 重要的是，随着美国人口老龄化，PFD 未来几十年将影响越来越多的女性，预计将有 4400 万女性到 2050.2，PFD 的巨大成本将以两倍的速度增长由于我们社会预期寿命的增加而增加人口。盆底肌肉（PFM）功能障碍是一种进展为症状性 PFD 的关键缺陷。3,4 尽管如此，PFD 的病理生理学和与年龄相关的 PFM 功能障碍的原因仍知之甚少。因此，目前尚无预防措施措施和现有治疗方法有限。特别是，PFM 康复对于老年女性效果较差，手术方法与高失败率和不良事件相关。5,6 因此，许多老年女性认为 PFD 是衰老过程中不可避免的一部分，但事实上她们应该要求更多。众所周知，衰老会导致肢体和身体部位的干细胞萎缩、纤维化和耗竭。躯干肌肉，导致与年龄相关的肌肉功能下降。7,8,9 然而，直接探测 PFM 并不由于它们位于骨盆深处，因此可行。当前有关 PFM 的知识主要来自传统的放射学检查因分辨率低且无法区分而受到影响收缩基质和细胞外基质成分之间的差异。10 作为替代方案，人类尸体标本可以可以用来开始建立与年龄相关的 PFM 功能障碍的机制。阐明与年龄相关的 PFD 和 PFM 功能障碍的发病机制的必要性是明确的：直到基本了解机制已经建立，治疗将带来边际希望，预防策略将继续不存在。我们建议确定功能上重要的与年龄相关的改变，与年龄相关的改变无关分娩的后果，在人类 PFM 的重要组成部分（肌纤维、细胞外基质、干细胞）中细胞）。我们将对从年轻和年长女性身上获得的尸体 PFM 进行直接检查未生育的捐赠者。这个项目将测试我们的总体假设，即与其他骨骼肌类似，年龄- 相关的萎缩、纤维化和干细胞库减少会对 PFM 偏移、力量产生产生负面影响，机械性能和再生。我们提出的细胞和组织水平研究是通过一种新颖的方法实现的其他学科的理论框架和进步的应用。这些高分辨率分析将促进创新且科学合理的预防性康复团的发展确定减轻与年龄相关的 PFM 功能障碍的新治疗靶点。最终，我们希望减轻 PFD 的负担并改善数百万老年妇女的生活。