title: Hypoxia-inducible factor 1-α induces miR-210 in normoxic differentiating myoblasts.
abstract: MicroRNA-210 (miR-210) induction is a virtually constant feature of the hypoxic response in both normal and transformed cells, regulating several key aspects of cardiovascular diseases and cancer. We found that miR-210 was induced in normoxic myoblasts upon myogenic differentiation both in vitro and in vivo. miR-210 transcription was activated in an hypoxia-inducible factor 1-α (Hif1a)-dependent manner, and chromatin immunoprecipitation experiments show that Hif1a bound to the miR-210 promoter only in differentiated myotubes. Accordingly, luciferase reporter assays demonstrated the functional relevance of the Hif1a binding site for miR-210 promoter activation in differentiating myoblasts. To investigate the functional relevance of increased miR-210 levels in differentiated myofibers, we blocked miR-210 with complementary locked nucleic acid oligonucleotides (anti-miR-210). We found that C2C12 myoblast cell line differentiation was largely unaffected by anti-miR-210. Likewise, miR-210 inhibition did not affect skeletal muscle regeneration following cardiotoxin damage. However, we found that miR-210 blockade greatly increased myotube sensitivity to oxidative stress and mitochondrial dysfunction. In conclusion, miR-210 is induced in normoxic myofibers, playing a cytoprotective role.
authors.affiliation: IRCCS-Policlinico San Donato, 20097 Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Cicchillitti
authors.forename: Valeria
authors.initials: V
authors.lastname: Di Stefano
authors.forename: Eleonora
authors.initials: E
authors.lastname: Isaia
authors.forename: Luca
authors.initials: L
authors.lastname: Crimaldi
authors.forename: Pasquale
authors.initials: P
authors.lastname: Fasanaro
authors.forename: Valeria
authors.initials: V
authors.lastname: Ambrosino
authors.forename: Annalisa
authors.initials: A
authors.lastname: Antonini
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaetano
authors.forename: Giulia
authors.initials: G
authors.lastname: Piaggio
authors.forename: Fabio
authors.initials: F
authors.lastname: Martelli
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C549325:MIRN210 microRNA, mouse; D035683:MicroRNAs; D010100:Oxygen