Mechanisms and impact of pregnancy-induced adaptations in pelvic floor muscles

项目总结 产妇分娩损伤是导致盆底肌肉功能障碍的主要危险因素 盆底疾病。尽管如此，交付前的个性化风险评估目前是不可能的，而且 PFM出生损伤对功能相关肌肉成分的影响还没有明确的定义。结果, 除了剖腹产之外，没有其他预防策略，可用的治疗方法也非常有限。 使用大鼠模型，我们最近发现在PFM中存在妊娠诱导的适应， 具体地说，通过连续添加肌节或肌瘤发生来延长纤维，并改变 细胞外基质(ECM)含量和肌肉僵硬。这些重要的发现使我们总体上 假设1)妊娠诱导的适应使PFM准备好承受机械需求 与分娩有关，以及2)当这些适应不足或超过时，对 随之而来的是全氟甲烷。我们将使用大鼠模型，在三个独立但相互关联的目标上测试这些假设。目标 1将重点确定金属烤瓷的妊娠适应对机械损伤的保护作用。 产伤及产伤对产后肌肉恢复的影响。使用怀孕晚期、未怀孕、和 怀孕中期的大鼠，我们将确定PFMS对菌株的急性和长期反应，当 妊娠诱导的适应要么存在，要么不存在，要么不完全。目标2将侧重于机制 在PFM中驱动妊娠诱导的适应，假设更大的机械负荷来自于 子宫增大，再加上孕期的荷尔蒙环境，会导致肌瘤形成，增加细胞外基质。 内容，和更高的肌肉硬度。确定机械和机械的独立效应和联合效应 内分泌提示与妊娠相关的PFM可塑性，我们将使用单侧妊娠的大鼠和一种新的 单侧负重子宫角非妊娠大鼠模型。目标3将测试松弛素，一种关键的 妊娠激素被推测为调节肌瘤发生和肌肉内细胞外基质 重建，对于妊娠诱导的全卵泡巨噬细胞的适应是必要的。我们将中和内源性 妊娠大鼠的松弛素及松弛素剥夺对收缩、细胞外基质和细胞的影响 全氟甲烷的组成部分。然后，我们将给有体重和无体重的非怀孕动物注射松弛素 加载子宫角，以测试松弛素是否足以单独或与PFM一起驱动PFM适应 机械负荷增加。这些目标将共同阐明怀孕和分娩对PFM的影响。 机械性能、适应性和再生性。这些创新实验的结果将成为 制定最大限度地保护适应和再生的新战略框架 盆底肌肉。如果成功，这种策略可能会将目前的临床模式转向预防 产伤后盆底肌肉损伤的保护与恢复治疗 肌肉，这两个都是女性骨盆医学取得有意义进展所必需的。

PROJECT SUMMARY Maternal childbirth injury is the leading risk factor for pelvic floor muscle (PFM) dysfunction and the resultant pelvic floor disorders. Despite this, individualized risk assessment prior to delivery is currently not possible and the impact of PFM birth injury on the functionally relevant muscle components is not well defined. As a result, there are no preventative strategies beyond Cesarean section and available treatments are severely limited. Using the rat model, we recently discovered the existence of pregnancy-induced adaptations in the PFMs, specifically fiber elongation via serial addition of sarcomeres, or sarcomerogenesis, and changes in extracellular matrix (ECM) content and muscle stiffness. These important discoveries led to our overall hypotheses that 1) pregnancy-induced adaptations prepare PFMs to withstand the mechanical demands associated with parturition, and 2) when these adaptations are either deficient or are exceeded, injury to the PFMs ensues. We will test these hypotheses in 3 independent but interrelated Aims, using the rat model. Aim 1 will focus on determining the protective effect of PFM pregnancy-induced adaptations against mechanical injury and the impact of birth injury on postpartum muscle recovery. Using late-pregnant, non-pregnant, and mid-pregnant rats, we will determine the acute and long-term response of the PFMs to strains, when pregnancy-induced adaptations are either present, absent, or incomplete. Aim 2 will focus on the mechanisms that drive pregnancy-induced adaptations in the PFMs, with the hypothesis that greater mechanical load from the enlarged uterus, combined with hormonal milieu of pregnancy, lead to sarcomerogenesis, increased ECM content, and higher muscle stiffness. To determine the independent and combined effects of mechanical and endocrine cues associated with pregnancy on PFM plasticity, we will use unilaterally pregnant rats and a novel non-pregnant rat model with unilaterally weight-loaded uterine horns. Aim 3 will test whether relaxin, a critical pregnancy hormone that has been speculated to regulate sarcomerogenesis and intramuscular ECM remodeling, is necessary for pregnancy-induced adaptations in the PFMs. We will neutralize endogenous relaxin in pregnant rats and assess the influence of relaxin deprivation on the contractile, ECM, and cellular components of the PFMs. We will then administer relaxin to non-pregnant animals with and without weight loaded uterine horns, to test whether relaxin is sufficient to drive PFM adaptations alone or in conjunction with increased mechanical load. Together, these Aims will elucidate the impact of pregnancy and delivery on PFM mechanical, adaptive and regenerative properties. The results of these innovative experiments will serve as a framework for the development of novel strategies for maximizing protective adaptations and regeneration in pelvic floor muscles. If successful, such strategies could shift the current clinical paradigm towards prevention of pelvic floor muscle birth trauma and treatments that preserve and restore postpartum function of injured muscles, both of which are essential for meaningful advances to occur in female pelvic medicine.