Mfge8 attenuates human gastric antrum smooth muscle contractions

Wen Li,Andrew J Syder,Cristina Alexandru,Brian A Perrino,Jill Wykosky,Andrew Outland,Ashley Olseen,Angela F Herrera,Yeming Xie

doi:10.1007/s10974-021-09604-y

Abstract

Coordinated gastric smooth muscle contraction is critical for proper digestion and is adversely affected by a number of gastric motility disorders. In this study we report that the secreted protein Mfge8 (milk fat globule-EGF factor 8) inhibits the contractile responses of human gastric antrum muscles to cholinergic stimuli by reducing the inhibitory phosphorylation of the MYPT1 (myosin phosphatase-targeting subunit (1) subunit of MLCP (myosin light chain phosphatase), resulting in reduced LC20 (smooth muscle myosin regulatory light chain (2) phosphorylation. Mfge8 reduced the agonist-induced increase in the F-actin/G-actin ratios of β-actin and γ-actin1. We show that endogenous Mfge8 is bound to its receptor, α8β1 integrin, in human gastric antrum muscles, suggesting that human gastric antrum muscle mechanical responses are regulated by Mfge8. The regulation of gastric antrum smooth muscles by Mfge8 and α8 integrin functions as a brake on gastric antrum mechanical activities. Further studies of the role of Mfge8 and α8 integrin in regulating gastric antrum function will likely reveal additional novel aspects of gastric smooth muscle motility mechanisms.

Highlights

Digestion of ingested food by the stomach involves accommodation, chemical and mechanical disruption of solids into chyme, and controlled emptying into the duodenum
Human gastric antrum muscles contain α8β1 integrin heterodimers and Mfge8. Because it was reported by Khalifeh-Soltani et al (2016) that Mfge8 binds to α8 integrin in α8β1 integrin heterodimers in murine gastric antrum muscles, we used in situ proximity ligation assay (PLA)
The PLA results and β1 integrin immunostaining in Fig. 2B show that Mfge8 is likely bound to α8 integrin in human gastric antrum smooth muscles

Summary

Introduction

Digestion of ingested food by the stomach involves accommodation, chemical and mechanical disruption of solids into chyme, and controlled emptying into the duodenum. To carry out these functions, the stomach is comprised of functional anatomic regions with distinct motility patterns (Kong and Singh 2008; Janssen et al 2011). Healthy gastric function depends on properly coordinated motor activities. Animal models have been studied for many years, but the regulatory mechanisms underlying the motor activities of the human stomach are not as well understood (Goyal et al 2019; Tack et al 2019)

Methods

Results

Conclusion