TLR9和Beclin 1协同调节运动时肌肉AMPK激活
2020-02-14   阅读:215   来源:自然

2020年2月12日,美国德克萨斯大学西南医学中心Beth Levine、Yang Liu等研究人员合作在《自然》发表论文。他们的最新工作发现,TLR9和Beclin 1协同调节运动时肌肉AMPK激活。

研究人员报道了先天性免疫感应分子Toll样受体9(TLR9)及其与beclin 1的相互作用在运动诱导的骨骼肌AMPK激活中的作用。缺乏TLR9的小鼠在运动诱导的AMPK激活和骨骼肌GLUT4葡萄糖转运蛋白的质膜定位方面均显示出不足,但在自噬方面没有缺陷。TLR9与beclin 1结合,这种相互作用因能量压力(葡萄糖饥饿和耐力运动)而增加,而由于BCL2突变(阻止BCL2与beclin 1的结合)而减少。TLR9调节运动期间骨骼肌中的溶酶体磷脂酰肌醇3激酶复合物(PI3KC3-C2)的组装,该复合物包含beclin 1和UVRAG,因此,敲除beclin 1或UVRAG会抑制葡萄糖饥饿诱导的细胞AMPK激活。此外,TLR9在体外收缩诱导的AMPK活化、葡萄糖摄取和Beclin 1-UVRAG复合物装配中以肌肉自主方式发挥作用。这些发现揭示了运动过程中Toll样受体在骨骼肌AMPK激活和葡萄糖代谢中的新作用,也揭示了先天免疫传感器与自噬蛋白之间的新交流。
 
据了解,骨骼肌中AMPK的激活协调对运动的全身代谢反应。自噬是一种维持细胞稳态的溶酶体降解途径,在运动过程中被上调,而核心自噬蛋白beclin 1是骨骼肌中AMPK激活所必需的。
 
附:英文原文

Title: TLR9 and beclin 1 crosstalk regulates muscle AMPK activation in exercise

Author: Yang Liu, Phong T. Nguyen, Xun Wang, Yuting Zhao, Corbin E. Meacham, Zhongju Zou, Bogdan Bordieanu, Manuel Johanns, Didier Vertommen, Tobias Wijshake, Herman May, Guanghua Xiao, Sanae Shoji-Kawata, Mark H. Rider, Sean J. Morrison, Prashant Mishra, Beth Levine

Issue&Volume: 2020-02-12

Abstract: The activation of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle coordinates systemic metabolic responses to exercise1. Autophagy—a lysosomal degradation pathway that maintains cellular homeostasis2—is upregulated during exercise, and a core autophagy protein, beclin 1, is required for AMPK activation in skeletal muscle3. Here we describe a role for the innate immune-sensing molecule Toll-like receptor 9 (TLR9)4, and its interaction with beclin 1, in exercise-induced activation of AMPK in skeletal muscle. Mice that lack TLR9 are deficient in both exercise-induced activation of AMPK and plasma membrane localization of the GLUT4 glucose transporter in skeletal muscle, but are not deficient in autophagy. TLR9 binds beclin 1, and this interaction is increased by energy stress (glucose starvation and endurance exercise) and decreased by a BCL2 mutation3,5 that blocks the disruption of BCL2–beclin 1 binding. TLR9 regulates the assembly of the endolysosomal phosphatidylinositol 3-kinase complex (PI3KC3-C2)—which contains beclin 1 and UVRAG—in skeletal muscle during exercise, and knockout of beclin 1 or UVRAG inhibits the cellular AMPK activation induced by glucose starvation. Moreover, TLR9 functions in a muscle-autonomous fashion in ex vivo contraction-induced AMPK activation, glucose uptake and beclin 1–UVRAG complex assembly. These findings reveal a heretofore undescribed role for a Toll-like receptor in skeletal-muscle AMPK activation and glucose metabolism during exercise, as well as unexpected crosstalk between this innate immune sensor and autophagy proteins.

DOI: 10.1038/s41586-020-1992-7

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