Exercise improves homeostasis of the intestinal epithelium by activation of APJ-AMPK signaling.

Intestinal remodeling is dynamically regulated by energy metabolism. Exercise is beneficial for gut health, but the specific mechanisms remain poorly understood. Both intestine-specific apelin receptor (APJ) knockdown (KD) and wild-type male mice were randomly divided into two subgroups with/without exercise to obtain four groups: WT, WT with exercise, APJ KD, and APJ KD with exercise. Animals in exercise groups were subjected to daily treadmill exercise for 3 weeks. Duodenum was collected at 48h after the last bout of exercise. AMP-activated protein kinase (AMPK) α1 KD and wild-type mice were also utilized for investigating the mediatory role of AMPK on exercise-induced duodenal epithelial development. AMPK and peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1 α) were upregulated by exercise via APJ activation in the intestinal duodenum. Correspondingly, exercise induced permissive histone modifications in the PR domain containing 16 (PRDM16) promoter to activate its expression, which was dependent on APJ activation. In agreement, exercise elevated the expression of mitochondrial oxidative markers. The expression of intestinal epithelial markers was downregulated due to AMPK deficiency, and AMPK signaling facilitated epithelial renewal. These data demonstrate that exercise-induced activation of APJ-AMPK axis facilitates the homeostasis of the intestinal duodenal epithelium. ONE-SENTENCE SUMMARY: Exercise-induced APJ-AMPK axis upregulated the expression of PGC-1α and PRDM16 to improve homeostasis of intestinal epithelium. KEY POINTS: APJ signaling is required for improved epithelial homeostasis of the small intestine in response to exercise. Exercise intervention activates PRDM16 through inducing histone modifications, improving mitochondrial biogenesis and fatty acid metabolism in duodenum. Structure of intestinal epithelium is improved by muscle-derived exerkine apelin through APJ-AMPK axis. Abstract figure legend. Exercise training increases expression of apelin in muscle and the circulating apelin level. Exercise-induced apelin-APJ signaling enhances villus and crypt structure of the small intestine (duodenum) through the activation of AMPK and stimulation of mitochondrial biogenesis. Of note, exercise program induces histone modifications for PRDM16 expression, which enhances mitochondrial oxidative metabolism, thereby improving intestinal epithelial homeostasis. This article is protected by copyright. All rights reserved.