title: Myostatin-induced inhibition of the long noncoding RNA Malat1 is associated with decreased myogenesis.
abstract: Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily of secreted proteins, is a potent negative regulator of myogenesis. Free myostatin induces the phosphorylation of the Smad family of transcription factors, which, in turn, regulates gene expression, via the canonical TGF-β signaling pathway. There is, however, emerging evidence that myostatin can regulate gene expression independent of Smad signaling. As such, we acquired global gene expression data from the gastrocnemius muscle of C57BL/6 mice following a 6-day treatment with recombinant myostatin compared with vehicle-treated animals. Of the many differentially expressed genes, the myostatin-associated decrease (-11.20-fold; P < 0.05) in the noncoding metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was the most significant and the most intriguing because of numerous reports describing its novel role in regulating cell growth. We therefore sought to further characterize the role of Malat1 expression in skeletal muscle myogenesis. RT-PCR-based quantification of C2C12 and primary human skeletal muscle cells revealed a significant and persistent upregulation (4- to 7-fold; P < 0.05) of Malat1 mRNA during the differentiation of myoblasts into myotubes. Conversely, targeted knockdown of Malat1 using siRNA suppressed myoblast proliferation by arresting cell growth in the G(0)/G(1) phase. These results reveal Malat1 as novel downstream target of myostatin with a considerable ability to regulate myogenesis. The identification of new targets of myostatin will have important repercussions for regenerative biology through inhibition and/or reversal of muscle atrophy and wasting diseases.
authors.affiliation: Faculty of Kinesiology, University of Calgary, Calgary, Canada.
authors.forename: Rani
authors.initials: R
authors.lastname: Watts
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Johnsen
authors.forename: Jane
authors.initials: J
authors.lastname: Shearer
authors.forename: Dustin S
authors.initials: DS
authors.lastname: Hittel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal; D018482:Muscle, Skeletal / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D055435:Myostatin / Q000378:metabolism* / Q000494:pharmacology; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: C557041:MALAT1 long non-coding RNA, human; D055435:Myostatin; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins
keywords: Malat1; microarray; myogenesis; myostatin