title: microRNA for determining the age-related myogenic capabilities of skeletal muscle.
abstract: Skeletal muscle exhibits a loss of muscle mass and function with age. Decreased regenerative potential of muscle stem/progenitor cells is a major underlying cause of sarcopenia. We analyzed microRNAs (miRNA) that are differentially expressed in young and old myoblasts, to identify novel intrinsic factors that play a degenerative role in aged skeletal muscle. miR-431, one of decreasing miRNAs in old myoblasts, improved the myogenic differentiation when overexpressed in old myoblast, but suppressed their myogenic capability in knockdowned young myoblasts. We found that miR-431 directly binds to 3`untranslated regions (UTR) of Smad4 mRNA, and decreases its expression. Given that SMAD4 is one of the downstream effectors of TGF-β, a well-known degenerative signaling pathway in myogenesis, the decreased miR-431 in old myoblast causes SMAD4 elevation, thus resulting in defective myogenesis. Exogenous expression of miR-431 greatly improved the muscle regeneration in the cardiotoxin-injured hindlimb muscle of old mice by reducing SMAD4 levels. Since the miR-431 seed sequence is conserved in human SMAD4 3'UTR, miR-431 regulates the myogenic capacity of human skeletal myoblasts in the same manner. Our results suggest that age-associated miR-431 is required for the maintenance of the myogenic capability in myoblasts, thus underscoring its potential as a therapeutic target to slow down muscle aging.
authors.affiliation: Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
authors.forename: Kwang-Pyo
authors.initials: KP
authors.lastname: Lee
authors.affiliation: Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141; Department of Functional Genomics, Korea University of Science and Technology, Daejeon 34113, Korea.
authors.forename: Yeo Jin
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141; Department of Functional Genomics, Korea University of Science and Technology, Daejeon 34113, Korea.
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Kwon
mesh_terms: D000367:Age Factors; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D020869:Gene Expression Profiling; D051379:Mice; D035683:MicroRNAs / Q000032:analysis* / Q000378:metabolism; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D032446:Myoblasts / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C573122:MIRN431 microRNA, human; D035683:MicroRNAs; C497796:SMAD4 protein, human; D051901:Smad4 Protein