Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA, USA.
Laboratory of Perinatal Kinesioepigenetics, Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
J Physiol. 2023 Jun;601(12):2371-2389. doi: 10.1113/JP284552. Epub 2023 May 16.
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.
肠道重塑受能量代谢的动态调控。运动有益于肠道健康，但具体机制仍知之甚少。肠特异性阿片肽受体（APJ）敲低（KD）和野生型雄性小鼠被随机分为两组，有/无运动，共获得四组：WT、WT 运动、APJ KD 和 APJ KD 运动。运动组动物每天进行跑步机运动 3 周。最后一次运动后 48 小时收集十二指肠。还利用 AMP 激活蛋白激酶（AMPK）α1 KD 和野生型小鼠来研究 AMPK 在运动诱导的十二指肠上皮发育中的中介作用。运动通过 APJ 激活在肠道十二指肠中上调 AMPK 和过氧化物酶体增殖物激活受体γ共激活因子 1α。相应地，运动诱导 PR 结构域包含 16（PRDM16）启动子中的允许性组蛋白修饰，以激活其表达，这依赖于 APJ 激活。一致地，运动提高了线粒体氧化标志物的表达。由于 AMPK 缺乏，肠上皮标志物的表达下调，而 AMPK 信号促进上皮更新。这些数据表明，运动诱导的 APJ-AMPK 轴的激活促进了肠道十二指肠上皮的稳态。关键点：APJ 信号对于运动引起的小肠上皮稳态改善是必需的。运动干预通过诱导组蛋白修饰、增强十二指肠中的线粒体生物发生和脂肪酸代谢来激活 PRDM16。肌肉衍生的外泌素阿片肽通过 APJ-AMP 激活蛋白激酶轴增强十二指肠绒毛和隐窝的形态发育。
