title: MicroRNA-23a and MicroRNA-27a Mimic Exercise by Ameliorating CKD-Induced Muscle Atrophy.
abstract: Muscle atrophy is a frequent complication of CKD, and exercise can attenuate the process. This study investigated the role of microRNA-23a (miR-23a) and miR-27a in the regulation of muscle mass in mice with CKD. These miRs are located in a gene cluster that is regulated by the transcription factor NFAT. CKD mice expressed less miR-23a in muscle than controls, and resistance exercise (muscle overload) increased the levels of miR-23a and miR-27a in CKD mice. Injection of an adeno-associated virus encoding the miR-23a/27a/24-2 precursor RNA into the tibialis anterior muscles of normal and CKD mice led to increases in mature miR-23a and miR-27a but not miR-24-2 in the muscles of both cohorts. Overexpression of miR-23a/miR-27a in CKD mice attenuated muscle loss, improved grip strength, increased the phosphorylation of Akt and FoxO1, and decreased the activation of phosphatase and tensin homolog (PTEN) and FoxO1 and the expression of TRIM63/MuRF1 and FBXO32/atrogin-1 proteins. Provision of miR-23a/miR-27a also reduced myostatin expression and downstream SMAD-2/3 signaling, decreased activation of caspase-3 and -7, and increased the expression of markers of muscle regeneration. Lastly,in silicomiR target analysis and luciferase reporter assays in primary satellite cells identified PTEN and caspase-7 as targets of miR-23a and FoxO1 as a target of miR-27a in muscle. These findings provide new insights about the roles of the miR-23a/27a-24-2 cluster in CKD-induced muscle atrophy in mice and suggest a mechanism by which exercise helps to maintain muscle mass.
authors.affiliation: Department of Medicine, Renal Division, Emory University, Atlanta, Georgia.|Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Medicine, Renal Division, Emory University, Atlanta, Georgia.|Division of Nephrology, China-Japan Friendship Hospital, Beijing, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Renal Division, Emory University, Atlanta, Georgia.|Department of Pediatric Nephrology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China; and.
authors.forename: Aiqing
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Renal Division, Emory University, Atlanta, Georgia.|Research Service Line, Atlanta Veterans Affairs Medical Center, Decatur, Georgia.
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Medicine, Renal Division, Emory University, Atlanta, Georgia.|Research Service Line, Atlanta Veterans Affairs Medical Center, Decatur, Georgia.
authors.forename: S Russ
authors.initials: SR
authors.lastname: Price
authors.affiliation: Department of Medicine, Renal Division, Emory University, Atlanta, Georgia; xwang03@emory.edu.
authors.forename: Xiaonan H
authors.initials: XH
authors.lastname: Wang
mesh_terms: D000818:Animals; D001284:Atrophy / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology*; D055435:Myostatin / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D010805:Physical Conditioning, Animal / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D014161:Transduction, Genetic; D000070584:Tripartite Motif Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D016207:Cytokines; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; C529080:Mirn24 microRNA, mouse; C540674:Mirn27 microRNA, mouse; C525912:Mstn protein, mouse; D009124:Muscle Proteins; D055435:Myostatin; D012333:RNA, Messenger; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D000070584:Tripartite Motif Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D053148:Caspase 3; D053179:Caspase 7
keywords: FBXO32/atrogin; TRIM63/MuRF1; exosome; microRNA; uremia