title: miR-206 represses hypertrophy of myogenic cells but not muscle fibers via inhibition of HDAC4.
abstract: microRNAs regulate the development of myogenic progenitors, and the formation of skeletal muscle fibers. However, the role miRNAs play in controlling the growth and adaptation of post-mitotic musculature is less clear. Here, we show that inhibition of the established pro-myogenic regulator miR-206 can promote hypertrophy and increased protein synthesis in post-mitotic cells of the myogenic lineage. We have previously demonstrated that histone deacetylase 4 (HDAC4) is a target of miR-206 in the regulation of myogenic differentiation. We confirmed that inhibition of miR-206 de-repressed HDAC4 accumulation in cultured myotubes. Importantly, inhibition of HDAC4 activity by valproic acid or sodium butyrate prevented hypertrophy of myogenic cells otherwise induced by inhibition of miR-206. To test the significance of miRNA-206 as a regulator of skeletal muscle mass in vivo, we designed recombinant adeno-associated viral vectors (rAAV6 vectors) expressing miR-206, or a miR-206 "sponge," featuring repeats of a validated miR-206 target sequence. We observed that over-expression or inhibition of miR-206 in the muscles of mice decreased or increased endogenous HDAC4 levels respectively, but did not alter muscle mass or myofiber size. We subsequently manipulated miR-206 levels in muscles undergoing follistatin-induced hypertrophy or denervation-induced atrophy (models of muscle adaptation where endogenous miR-206 expression is altered). Vector-mediated manipulation of miR-206 activity in these models of cell growth and wasting did not alter gain or loss of muscle mass respectively. Our data demonstrate that although the miR-206/HDAC4 axis operates in skeletal muscle, the post-natal expression of miR-206 is not a key regulator of basal skeletal muscle mass or specific modes of muscle growth and wasting. These studies support a context-dependent role of miR-206 in regulating hypertrophy that may be dispensable for maintaining or modifying the adult skeletal muscle phenotype--an important consideration in relation to the development of therapeutics designed to manipulate microRNA activity in musculature.
authors.affiliation: Division of Metabolism and Obesity, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.forename: Claudia
authors.initials: C
authors.lastname: Beyer
authors.forename: Adam
authors.initials: A
authors.lastname: Hagg
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.forename: Patricio V
authors.initials: PV
authors.lastname: Sepulveda
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
mesh_terms: D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics*; D006984:Hypertrophy / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000201:enzymology / Q000473:pathology* / Q000502:physiology; D009133:Muscular Atrophy / Q000235:genetics
chemical_list: D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
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