Impact of Aging on Structure and Function of Pelvic Floor Muscles

项目总结 年龄是盆底疾病(PFDs)的关键危险因素，包括盆腔器官脱垂和尿液 还有大便失禁。这些常见的疾病干扰了老年妇女的健康，因为她们 对生活质量和相关疾病的负面影响1.人格障碍的患病率每增加20% 十年的寿命，80岁及以上的女性达到50%。2重要的是，随着美国人口老龄化，PFDs 将在未来几十年影响越来越多的女性，预计将有4400万女性 此外，私营部门的大量费用将以两倍的速度增长 由于我们社会预期寿命的增加，人口的数量也在增加。盆底肌功能障碍是一种 发展为症状性PFD的严重缺陷。3，4尽管如此，PFDs的病理生理学和 与年龄相关的PFM功能障碍的原因仍然知之甚少。因此，目前没有预防性的 措施和现有的治疗方法是有限的。特别是，烤瓷修复术在老年妇女中效果较差， 而手术方法与高失败率和不良事件有关。5、6因此，许多 老年女性接受PFD是衰老过程中不可避免的一部分，而实际上她们应该要求更多。 众所周知，衰老会导致四肢和四肢的常驻干细胞萎缩、纤维化和枯竭。 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不是 由于它们位于骨盆深处，因此是可行的。目前关于全氟甲烷的知识主要是从 因分辨率低和无法区分而受到影响的常规放射检查 在收缩和细胞外基质成分之间。10作为替代，人类身体标本可以 开始建立与年龄相关的PFM功能障碍的机制。 明确需要阐明与年龄相关的PFDs和PFM功能障碍的发病机制：直到基础 机制已经建立，治疗将提供边际希望，预防战略将继续 变得不存在。我们建议确定功能上重要的与年龄相关的改变，与 分娩的后果，在人类全氟甲烷的重要组成部分(肌纤维、细胞外基质、干 单元格)。我们将直接检验从年轻女性和老年女性身上获得的身体全氟甲烷 未经产的捐赠者。这个项目将测试我们的总体假设，即类似于其他骨骼肌，年龄- 相关的萎缩、纤维化和干细胞库的减少对烤瓷修复体的偏移、力量产生、 机械性能和再生。我们提出的细胞和组织水平的研究是由一种新的 理论框架的应用和其他学科的进步。这些高分辨率分析 将促进发展创新的和具有科学依据的预防性康复团体和 确定新的治疗靶点以减轻与年龄相关的PFM功能障碍。最终，我们希望 减轻老年妇女的负担，改善数百万老年妇女的生活。

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.