title: Transcription factor FoxO1, the dominant mediator of muscle wasting in chronic kidney disease, is inhibited by microRNA-486.
abstract: Chronic kidney disease (CKD) accelerates muscle protein degradation by stimulating the ubiquitin proteasome system through activation of the E3 ligases, Atrogin-1/MAFbx and MuRF-1. Forkhead transcription factors (FoxOs) can control the expression of these E3 ligases, but the contribution of individual FoxOs to muscle wasting is unclear. To study this we created mice with a muscle-specific FoxO1 deletion. The absence of FoxO1 blocked 70% of the increase in E3 ligase induction by CKD as well as the proteolysis and loss of muscle mass. Thus, FoxO1 has a role in controlling ubiquitin proteasome system-related proteolysis. As microRNA (miR)-486 reportedly dampens FoxO1 expression and its activity,we transfected a miR-486 mimic into primary cultures of myotubes and found this blocked dexamethasone-stimulated protein degradation without influencing protein synthesis.It also decreased FoxO1 protein translation and increased FoxO1 phosphorylation by downregulation of PTEN phosphatase, a negative regulator of p-Akt. To test its efficacy in vivo, we electroporated miR-486 into muscles and found that the expression of the E3 ligases was suppressed and muscle mass increased despite CKD. Thus, FoxO1 is a dominant mediator of CKD-induced muscle wasting, and miR-486 coordinately decreases FoxO1 and PTEN to protect against this catabolic response.
authors.affiliation: Renal Section, Changhai Hospital, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Rongshan
authors.initials: R
authors.lastname: Li
authors.forename: Biruh
authors.initials: B
authors.lastname: Workeneh
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Dong
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Hu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D018274:Electroporation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000096:biosynthesis / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009841:Oligonucleotides / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D005938:Glucocorticoids; C583982:MIRN486 microRNA, mouse; D035683:MicroRNAs; D009124:Muscle Proteins; D009841:Oligonucleotides; D000070584:Tripartite Motif Proteins; D003907:Dexamethasone; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D046988:Proteasome Endopeptidase Complex