Differences in Gastrointestinal Motility Between Males and Females in Health and Diabetes

Tuskegee University, Tuskegee Institute AL

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Abstract

Enter the text here that is the new abstract information for your application. Gastrointestinal (GI) motility differs between men and women. In women, GI motility varies with hormonal changes during the menstrual cycle and pregnancy. However, there is a gap in knowledge and understanding of the role of estrogen and the mechanisms by which it regulates differences in GI motility and dysmotility between males and cycling females. Unlike classical nuclear receptors ERα, ERβ, activation of membrane-bound G protein-coupled estrogen receptor (GPER) by estrogen initiates rapid cellular events. We have obtained preliminary evidence to show that GPER is expressed in smooth muscle and is coupled to AC/cAMP/PKA pathway to mediate muscle relaxation in the stomach and the colon. Smooth muscle from GPER KO mice exhibited loss of relaxation in response to GPER agonist, providing evidence for a role of GPER in smooth muscle relaxation. GI transit was delayed in female mice of high-estrogen proestrus and estrus phases compared to low-estrogen diestrus phase, and male mice. Differences in GI transit between males and cycling females, as well as cycle-dependent variations, are associated with changes in the expression and function of GPER. Based on these preliminary data, studies are proposed to test the hypothesis that differences in GI transit between males and females, as well as cycle-dependent changes are due to alterations in the expression and function of GPER coupled to activation of the AC/cAMP/PKA pathway and smooth muscle relaxation (Specific Aim 1). GI motility disorders also differ between men and women. There is a greater prevalence of diabetes-associated gastroparesis and constipation in women compared to men. The contribution of impaired smooth muscle function and the role of GPER in smooth muscle have not been fully explored in relation to differences between males and females in GI dysmotility associated with diabetes. Preliminary studies showed that expression of GPER was decreased in smooth muscle from diabetic mice and the decrease is mediated via oxidative stress-induced changes in epigenetic regulation via a decrease in trimethylation of H3 at lysine residue 4 (H3K4me3) and acetylation of H3 at lysine residue 27 (H3K27ac) at the promoter region of GPER gene. RNA-seq data combined with heatmap analysis showed an increase in the expression of selective histone deacetylase (HDACs) in smooth muscle from diabetic mice. An increase in oxidative stress was also obtained in smooth muscle from GPER KO mice suggesting the increase in oxidative stress in diabetes could be due to a decrease in GPER expression. Based on the preliminary data, studies ae proposed to test the hypothesis that an increase in oxidative stress in diabetes downregulates GPER expression via decrease in H3K4me3 and H3K27ac of GPER promoter, and loss of GPER-mediated protection against oxidative stress leads to decrease in cAMP/cGMP signaling, muscle relaxation and GI transit (Specific Aim 2). Our study elucidates the mechanisms underlying GI motility differences in males and cycling females. The higher prevalence of diabetes-associated GI dysmotility in females highlights the clinical importance of this research.