title: MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and Forkhead box j3.
abstract: MicroRNAs (miRNAs) are important posttranscriptional regulators of various biological pathways. In this study, we focused on the role of miRNAs during mitochondrial biogenesis in skeletal muscle. The expression of miR-494 was markedly decreased in murine myoblast C₂C₁₂ cells during myogenic differentiation, accompanied by an increase in mtDNA. Furthermore, the expression of predicted target genes for miR-494, including mitochondrial transcription factor A (mtTFA) and Forkhead box j3 (Foxj3), was posttranscriptionally increased during myogenic differentiation. Knockdown of miR-494 resulted in increased mitochondrial content and upregulation of mtTFA and Foxj3 at the protein level. A 3'-untranslated region reporter assay revealed that miR-494 knockdown directly upregulated the luciferase activity of mtTFA and Foxj3. All of these observations were reversed by overexpression of miR-494. Furthermore, the miR-494 content significantly decreased after endurance exercise in C57BL/6J mice, accompanied by an increase in expression of mtTFA and Foxj3 proteins. These results suggest that miR-494 regulates mitochondrial biogenesis by downregulating mtTFA and Foxj3 during myocyte differentiation and skeletal muscle adaptation to physical exercise.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Katsutaro
authors.initials: K
authors.lastname: Morino
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nishio
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ugi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshizaki
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D051858:Forkhead Transcription Factors; D017930:Genes, Reporter; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D063269:Mitochondrial Turnover; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C503717:FoxJ3 protein, mouse; D035683:MicroRNAs; C550178:Mirn494 microRNA, mouse; D024101:Mitochondrial Proteins; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A