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

妊娠引起的盆底肌肉适应的机制和影响

• 批准号: 9923711
• 负责人: Marianna Alperin
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923711
• 关键词: Acute; Anatomy; Animals; Architecture; Bilateral; Biochemical; Biological Factors; Biological Markers; Biomechanics; Birth; Birth trauma; Cesarean section; Characteristics; Childbirth; Clinical; Cues; Development; Economic Burden; Endocrine; Extracellular Matrix; Fecal Incontinence; Female; Fiber; Functional disorder; Future; Gene Expression; Goals; Hormonal; Hormones; Horns; Human; Injury; Intramuscular; Investigation; Knowledge; Lead; Length; Mechanics; Medicine; Metabolism; Modeling; Morbidity - disease rate; Muscle; Muscle Development; Natural regeneration; Pathogenesis; Pathway interactions; Pelvic Floor Disorders; Pelvic Floor Muscle; Pelvic floor dysfunction; Pelvic floor structure; Pelvis; Physiological; Postpartum Period; Pregnancy; Prevalence; Prevention; Prevention strategy; Procedures; Property; Public Health; Quality of life; Rattus; Recovery; Relaxin; Risk Assessment; Risk Factors; Role; Sarcomeres; Skeletal Muscle; Structure; Testing; Therapeutic Intervention; Tissues; Trauma; Urinary Incontinence; Uterus; Vagina; Vaginal delivery procedure; Weight; Woman; antenatal; cost; deprivation; epidemiology study; experimental study; imaging study; in vivo; injured; innovation; mechanical load; mechanical properties; mechanotransduction; muscle stiffness; novel; novel strategies; pelvic organ prolapse; pregnant; preservation; prevent; progenitor; protective effect; regenerative; response; satellite cell; stem cells; Acute; Anatomy; Animals; Architecture; Bilateral; Biochemical; Biological Factors; Biological Markers; Biomechanics; Birth; Birth trauma; Cesarean section; Characteristics; Childbirth; Clinical; Cues; Development; Economic Burden; Endocrine; Extracellular Matrix; Fecal Incontinence; Female; Fiber; Functional disorder; Future; Gene Expression; Goals; Hormonal; Hormones; Horns; Human; Injury; Intramuscular; Investigation; Knowledge; Lead; Length; Mechanics; Medicine; Metabolism; Modeling; Morbidity - disease rate; Muscle; Muscle Development; Natural regeneration; Pathogenesis; Pathway interactions; Pelvic Floor Disorders; Pelvic Floor Muscle; Pelvic floor dysfunction; Pelvic floor structure; Pelvis; Physiological; Postpartum Period; Pregnancy; Prevalence; Prevention; Prevention strategy; Procedures; Property; Public Health; Quality of life; Rattus; Recovery; Relaxin; Risk Assessment; Risk Factors; Role; Sarcomeres; Skeletal Muscle; Structure; Testing; Therapeutic Intervention; Tissues; Trauma; Urinary Incontinence; Uterus; Vagina; Vaginal delivery procedure; Weight; Woman; antenatal; cost; deprivation; epidemiology study; experimental study; imaging study; in vivo; injured; innovation; mechanical load; mechanical properties; mechanotransduction; muscle stiffness; novel; novel strategies; pelvic organ prolapse; pregnant; preservation; prevent; progenitor; protective effect; regenerative; response; satellite cell; stem cells

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.

项目摘要 产妇分娩是骨盆地板肌肉（PFM）功能障碍的主要危险因素，结果是 骨盆地板障碍。尽管如此，目前仍无法在交付前的个性化风险评估，并且 PFM出生损伤对功能相关的肌肉成分的影响尚未很好地定义。因此， 除剖宫产外，没有预防策略，可用的治疗受到严重限制。 使用大鼠模型，我们最近发现了PFMS中妊娠诱导的适应性的存在， 特异性通过肉瘤或肉瘤发生的连续添加以及变化的纤维伸长 细胞外基质（ECM）含量和肌肉刚度。这些重要的发现导致了我们的整体 假设1）怀孕诱导的适应性准备PFM以承受机械需求 与分娩相关，以及2）当这些适应不足或超过这些适应时， 随之而来的是PFM。我们将使用大鼠模型在3个独立但相互关联的目标中测试这些假设。目的 1将着重于确定PFM妊娠引起的针对机械的保护作用 受伤和出生损伤对产后肌肉恢复的影响。使用晚期，非怀孕和 妊娠大鼠，我们将确定PFMS对菌株的急性和长期反应，当 怀孕引起的适应性存在，不存在或不完整。 AIM 2将重点放在机制上 这推动了妊娠引起的PFMS的适应 子宫扩大，结合妊娠的荷尔蒙环境，导致肉瘤发生，增加了ECM 内容和更高的肌肉僵硬。确定机械和机械和联合效应 与PFM可塑性相关的内分泌线索，我们将使用单侧怀孕的大鼠和一种新颖 具有单侧重量子宫角的非怀孕大鼠模型。 AIM 3将测试放松，是否关键 据推测用于调节肉瘤发生和肌内ECM的妊娠激素 重塑，对于PFMS中妊娠诱导的适应性是必需的。我们将中和内源性 在怀孕大鼠中放松蛋白，并评估放松蛋白剥夺对收缩，ECM和细胞的影响 PFM的组件。然后，我们将对有或不重的非怀孕动物进行放松素 加载子宫角，以测试放松蛋白是否足以单独驱动PFM适应或与 机械负载增加。这些目标共同阐明了怀孕和递送对PFM的影响 机械，适应性和再生特性。这些创新实验的结果将作为 制定新型策略的框架，以最大化保护性适应和再生 骨盆地板肌肉。如果成功，此类策略可能会将当前的临床范式转移到预防上 骨盆底肌肉的出生创伤和治疗，可保留和恢复受伤的产后功能 肌肉，两者对于在女性骨盆医学中发生有意义的进步至关重要。