Exercise improves homeostasis of the intestinal epithelium by activation of apelin receptor-AMP-activated protein kinase signalling.

Intestinal remodelling is dynamically regulated by energy metabolism. Exercise is beneficial for gut health, but the specific mechanisms remain poorly understood. 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 the exercise groups were subjected to daily treadmill exercise for 3 weeks. Duodenum was collected at 48 h 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 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 signalling facilitated epithelial renewal. These data demonstrate that exercise-induced activation of the APJ-AMPK axis facilitates the homeostasis of the intestinal duodenal epithelium. KEY POINTS: Apelin receptor (APJ) signalling is required for improved epithelial homeostasis of the small intestine in response to exercise. Exercise intervention activates PRDM16 through inducing histone modifications, enhanced mitochondrial biogenesis and fatty acid metabolism in duodenum. The morphological development of duodenal villus and crypt is enhanced by the muscle-derived exerkine apelin through the APJ-AMP-activated protein kinase axis.