title: Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle.
abstract: Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of skeletal muscle growth and development. Myostatin inhibition leads to increased skeletal muscle mass in mammals; hence, myostatin is considered a potential therapeutic target for skeletal muscle wasting. However, downstream molecules of myostatin in the skeletal muscle have not been fully elucidated. Here, we identified the Dlk1-Dio3 locus at the mouse chromosome 12qF1, also called as the callipyge locus in sheep, as a novel downstream target of myostatin. In skeletal muscle of myostatin knockout mice, the expression of mature miRNAs at the Dlk1-Dio3 locus was significantly increased. The increased miRNA levels are caused by the transcriptional activation of the Dlk1-Dio3 locus, because a significant increase in the primary miRNA transcript was observed in myostatin knockout mice. In addition, we found increased expression of coding and non-coding genes (Dlk1, Gtl2, Rtl1/Rtl1as, and Rian) at the Dlk1-Dio3 locus in myostatin-deficient skeletal muscle. Moreover, epigenetic changes, associated with the regulation of the Dlk1-Dio3 locus, were observed in myostatin knockout mice. Taken together, this is the first report demonstrating the role of myostatin in regulating the Dlk1-Dio3 (the callipyge) locus in the skeletal muscle.
authors.affiliation: Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hitachi
authors.affiliation: Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Tsuchida
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002460:Cell Line; D033481:Chromosomes, Mammalian / Q000235:genetics; D044127:Epigenesis, Genetic; D056426:Genetic Loci; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007453:Iodide Peroxidase / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D055435:Myostatin / Q000172:deficiency*; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; C525912:Mstn protein, mouse; D055435:Myostatin; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase
keywords: IG-DMR ncRNA; callipyge; miRNA; myostatin; skeletal muscle