Background:Angiogenesis constitutes a major mechanism responsible for exercise-induced beneficial effects.Our previous study identified a cluster of differentially expressed extracellular vesicle microRNAs(miRNAs)after exercise and found that some of them act as exerkines.How-ever,whether these extracellular vesicle miRNAs mediate the exercise-induced angiogenesis remains unknown.Methods:A 9-day treadmill training was used as an exercise model in C57BL/6 mice.Liver-specific adeno-associated virus 8 was used to knock down microRNA-122-5p(miR-122-5p).Human umbilical vein endothelial cells were used in vitro.Results:Among these differentially expressed extracellular vesicle miRNAs,miR-122-5p was identified as a potent pro-angiogenic factor that activated vascular endothelial growth factor signaling and promoted angiogenesis both in vivo and in vitro.Exercise increased circulating levels of miR-122-5p,which was produced mainly by the liver and shuttled by extracellular vesicles in mice.Inhibition of circulating miR-122-5p or liver-specific knockdown of miR-122-5p significantly abolished the exercise-induced pro-angiogenic effect in skeletal muscles,and exercise-improved muscle performance in mice.Mechanistically,miR-122-5p promoted angiogenesis through shifting substrate preference to fatty acids in endothelial cells,and miR-122-5p upregulated endothelial cell fatty-acid utilization by targeting 1-acyl-sn-glycerol-3-phosphate acyltransfe-rase(AGPAT1).In addition,miR-122-5p increased capillary density in perilesional skin tissues and accelerated wound healing in mice.Conclusion:These findings demonstrated that exercise promotes angiogenesis through upregulation of liver-derived extracellular vesicle miR-122-5p,which enhances fatty acid utilization by targeting AGPAT1 in endothelial cells,highlighting the therapeutic potential of miR-122-5p in tissue repair.

Jing Lou;Jie Wu;Mengya Feng;Xue Dang;Guiling Wu;Hongyan Yang;Yan Wang;Jia Li;Yong Zhao;Changhong Shi;Jiankang Liu;Lin Zhao;Xing Zhang;Feng Gao

Center for Mitochondrial Biology and Medicine,The Key Laboratory of Biomedical Information Engineering of Ministry of Education,School of Life Science and Technology,Xi'an Jiaotong University,Xi'an 710049,China;School of Aerospace Medicine,Fourth Military Medical University,Xi'an 710032,China;Medical School of Chinese PLA,Beijing 100853,China;Laboratory Animal Center,Fourth Military Medical University,Xi'an 710032,China

运动与健康科学（英文）

[1]Jing Lou;Jie Wu;Mengya Feng;Xue Dang;Guiling Wu;Hongyan Yang;Yan Wang;Jia Li;Yong Zhao;Changhong Shi;Jiankang Liu;Lin Zhao;Xing Zhang;Feng Gao-.Exercise promotes angiogenesis by enhancing endothelial cell fatty acid utilization via liver-derived extracellular vesicle miR-122-5p)[J].运动与健康科学（英文）,2022(04):495-508

shuttled,acyltransfe,rase,AGPAT1,perilesional

Exercise,promotes,angiogenesis,by,enhancing,endothelial,fatty,utilization,via,liver,derived,extracellular,5p,Background,Angiogenesis,constitutes,major,mechanism,responsible,exercise,induced,beneficial,effects,Our,previous,study,identified,cluster,differentially,expressed,microRNAs,miRNAs,after,found,that,some,them,exerkines,How,ever,whether,these,mediate,remains,unknown,Methods,day,treadmill,training,was,used,model,C57BL,mice,Liver,specific,adeno,associated,virus,Human,umbilical,vein,cells,were,vitro,Results,Among,angiogenic,activated,vascular,growth,signaling,promoted,both,vivo,increased,circulating,levels,which,produced,mainly,vesicles,Inhibition,knockdown,significantly,abolished,skeletal,muscles,improved,performance,Mechanistically,through,shifting,substrate,preference,acids,upregulated,targeting,sn,glycerol,phosphate,addition,capillary,density,skin,tissues,accelerated,wound,healing,Conclusion,These,findings,demonstrated,upregulation,enhances,highlighting,therapeutic,potential,repair

0.483372