MicroRNA-29 induces cellular senescence in aging muscle through multiple signaling pathways

• Type of Material: Article
• Authors: Zhaoyong Hu, Baylor College of Medicine; Janet Klein, Emory University; William E. Mitch, Baylor College of Medicine; Liping Zhang, Baylor College of Medicine; Ivan Martinez, West Virginia University; Xiaonan Wang, Emory University
• Language: English
• Date: 2014-03-01
• Publisher: IMPACT JOURNALS LLC
• Publication Version: Final Published Version
• Copyright Statement: © Hu et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.18632/aging.100643
• Title of Journal or Parent Work: AGING-US
• Volume: 6
• Issue: 3
• Start Page: 160
• End Page: 175
• Grant/Funding Information: This work was supported by NIAMS 1R01AR060268 and the National Natural Science Foundation of China (30971471) to X.W; NIH R37 DK37175 to W. E. M.; the Virology & Drug Discovery Core of the Emory University for AIDS Research (P30 AI050409) and NIH P01 CA16038 to Daniel DiMaio (Yale University) and NIH AR 063686 to Z. Hu.
• Keywords: WNT; DNA-DAMAGE; p85; p50; BIOMARKER; DIFFERENTIATION; B-MYB; Science & Technology; IGF-1; HEMATOPOIETIC STEM-CELL; Life Sciences & Biomedicine; sarcopenia; SKELETAL-MUSCLE; Geriatrics & Gerontology; B-myb; p16lnk4A; RB; MIR-29; IGF-I; Cell Biology; EXPRESSION
• Research Categories: Biology, Genetics; Gerontology

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-ßgal 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.