Research Paper Volume 6, Issue 3 pp 160—175

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

Zhaoyong Hu 2, , Janet D. Klein 1, , William E. Mitch 2, , Liping Zhang 2, , Ivan Martinez 3, , Xiaonan H. Wang 1, ,

  • 1 Renal Division, Department of Medicine, Emory University, Atlanta, GA 30322, USA
  • 2 Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
  • 3 Immunology and Cell Biology, Department of Microbiology, West Virginia University, Morgantown, WV 26506, USA

received: November 25, 2013 ; accepted: March 11, 2014 ; published: March 12, 2014 ;

https://doi.org/10.18632/aging.100643
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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.

Abbreviations

miR-29: microRNA 29; RB: Retinoblastoma protein; SA-βgal: senescence-associated β-galactosidase; p16Ink4A: inhibitor of the proliferative kinase Cdk4 protein 16.