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.

PROJECT NARRATIVE: Pelvic floor disorders, which include pelvic organ prolapse, and urinary and fecal incontinence, are common and costly conditions that negatively impact the quality of life of millions of women. Childbirth associated injury and subsequent dysfunction of the pelvic floor muscles are believed to be critical for the pathogenesis of pelvic floor disorders. The goal of this project is to determine whether pregnancy-induced structural and mechanical adaptations in the pelvic floor muscles protect them from birth injury and to elucidate mechanisms that govern pelvic floor muscles’ plasticity during pregnancy.