title: MicroRNA-29 induces cellular senescence in aging muscle through multiple signaling pathways.
abstract: The mechanisms underlying the development of aging-induced muscle atrophy are unclear. By microRNA array and individual qPCR analyses, we found significant up-regulation of miR-29 in muscles of aged rodents vs. results in young. With aging, p85α, IGF-1 and B-myb muscle levels were lower while the expression of certain cell arrest proteins (p53, p16 and pRB) increased. When miR-29 was expressed in muscle progenitor cells (MPC), their proliferation was impaired while SA-βgal expression increased signifying the development of senescence. Impaired MPC proliferation resulted from interactions between miR-29 and the 3'-UTR of p85a, IGF-1 and B-myb, suppressing the translation of these mediators of myoblast proliferation. In vivo, electroporation of miR-29 into muscles of young mice suppressed the proliferation and increased levels of cellular arrest proteins, recapitulating aging-induced responses in muscle. A potential stimulus of miR-29 expression is Wnt-3a since we found that exogenous Wnt-3a stimulated miR-29 expression 2.7-fold in primary cultures of MPCs. Thus, aging-induced muscle senescence results from activation of miR-29 by Wnt-3a leading to suppressed expression of several signaling proteins (p85α, IGF-1 and B-myb) that act coordinately to impair the proliferation of MPCs contributing to muscle atrophy. The increase in miR-29 provides a potential mechanism for aging-induced sarcopenia.
authors.affiliation: Renal Division, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Hu
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Ivan
authors.initials: I
authors.lastname: Martinez
authors.forename: Xiaonan H
authors.initials: XH
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D032448:Myoblasts, Skeletal / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D051381:Rats; D011916:Rats, Inbred F344; D055948:Sarcopenia / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D060509:Wnt3A Protein / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C547014:MIRN29 microRNA, mouse; C526366:MIRN29 microRNA, rat; D035683:MicroRNAs; C498883:Mybl2 protein, rat; D014157:Transcription Factors; D060509:Wnt3A Protein; D007334:Insulin-Like Growth Factor I; D058543:Class Ia Phosphatidylinositol 3-Kinase