Metabolic mechanisms of uterine contractility in labor

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PROJECT SUMMARY/ABSTRACT Maternal obesity is associated with lower rates of spontaneous labor, slower progress of cervical dilation, and increased risks of labor arrest disorders and induction failure. Additionally, compared to lean women, women with obesity have a nearly three-fold higher rate of cesarean delivery, putting them at increased risk of maternal and neonatal morbidity. While the association between maternal obesity and abnormal labor has been well documented, the mechanisms responsible for this remain unknown. Evidence suggests that obesity causes uterine contractility dysfunction in women. Uterine smooth muscle (myometrium) from women with obesity contracts with less force and frequency than myometrium from normal-weight women and women with obesity require higher doses of oxytocin to achieve a vaginal delivery, suggesting abnormal contractile response. We developed a mouse model of diet-induced obesity that recapitulates the dysfunctional labor patterns seen in women with obesity and can be applied for further mechanistic studies. Here, our objective is to provide a mechanistic understanding of myometrial energy metabolism in control and obese mice during parturition. We focus on energy metabolism because the contractility required for cervical dilation and expulsion of the fetus during labor – lasting for hours to days in humans – places a high energy demand on the myometrium. Our preliminary data also suggest that obese dams have significantly higher lipid (triglyceride and fatty acids) content, increased expression of genes responsible for fatty acid uptake and storage, dysfunctional glycolytic flux, and decreased expression of a key glucose transporter in the myometrium than control dams at term. Thus, our overall hypothesis is that excess fatty acid and triglycerides in the myometrium of obese dams inhibit glucose oxidation, which is required for initiation and progression of early labor. Despite the fact that millions of women deliver an infant each year, we know surprisingly little about how the myometrium meets its energy demands in healthy women or those with obesity. The goals of this project are to (1) define the effects of diet-induced obesity on spontaneous and agonist-induced myometrial contractility and parturition in mice and (2) determine the effects of myometrial energy substrate availability on uterine contractility during labor in the mouse. Our proposed research will provide the necessary mechanistic data to develop pharmacologic and behavioral interventions to optimize myometrial energy storage and utilization during labor. Ultimately, this research may allow us to improve obstetric outcomes for millions of women with obesity.