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

• 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
• 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

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.

项目摘要 衰老是骨盆底疾病（PFD）的关键危险因素，其中包括骨盆脱垂和尿液 和粪便尿失禁。这些常见条件干扰了老年妇女的福祉 对生活质量和相关病因的负面影响。1PFD的患病率每种流行率增加了20％ 生命十年，在80岁及以上的女性中达到50％。2重要的是，随着美国人口的老龄化，PFD 在接下来的几十年中，将影响越来越多的妇女，预计有4400万妇女 此外，在2050.2之前，PFD遭受了PFD的巨额成本，将以两倍的速度增长 由于我们社会的预期寿命增加而导致的人口。骨盆底肌（PFM）功能障碍是 尽管如此 与年龄相关的PFM功能障碍的原因知之甚少。结果，目前没有预防性 措施和现有治疗是有限的。特别是，PFM康复在老年妇女中的效果较差， 手术方法与高失败率和不良事件有关。5,6因此，许多 老年妇女接受PFD是不可避免的衰老部分，而实际上她们应该要求更多。 众所周知，衰老会导致肢体中居民干细胞的萎缩，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但是，直接探测PFM不是 由于它们的位置在骨盆内部深处，因此可行。当前有关PFM的知识主要来自 传统的放射学检查受到低分辨率和无法区分的损害 在收缩和细胞外基质组件之间。10作为替代品，人尸体标本可以 要利用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功能障碍的发病机理的需求是明显的：直到基本 建立机制，治疗将提供边际承诺，预防策略将继续 不存在。我们建议确定与年龄相关的重要变化，与 分娩的后果，在人类PFM的重要组成部分（肌纤维，细胞外基质，茎） 细胞）。我们将直接检查从年轻女性和年龄较大的女性获得的尸体PFM 无效的捐助者。该项目将检验我们的总体假设，即类似于其他骨骼肌，年龄 - 相关的萎缩，纤维化和干细胞储层减少对PFM偏移，力产生， 机械性能和再生。我们提出的细胞和组织水平研究由新颖 其他学科的理论框架和进步的应用。这些高分辨率分析 将促进创新和科学原理预防性康复团的发展 鉴定新的治疗靶标可缓解与年龄相关的PFM功能障碍。最终，我们希望 减轻PFD的负担并改善数百万年长的妇女的生活。