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.

Wnt/β-Catenin Signaling Contributes to Skeletal Myopathy in Heart Failure via Direct Interaction With Forkhead Box O

“…13 Recent studies have indicated that Wnt signaling also plays an important role in skeletal muscle atrophy and regeneration. 14,22 In this study, we have demonstrated that both Wnt signaling and FoxO signaling are activated in skeletal muscle of DCM mice. We have also shown that Wnt signaling promotes FoxO1 nuclear translocation without affecting its phosphorylation level and increases the expression of FoxO target genes in cultured skeletal muscle cells.…”

“…22 We found that the expression of a Wnt/β-catenin/TCF/LEF target gene Axin2 and the nuclear amount of β-catenin were increased in the skeletal muscle of DCM mice ( Figure 2C and 2D), suggesting that Wnt signaling as well as FoxO signaling is activated in the skeletal muscle of DCM mice. …”

Are there roles for brain cell senescence in aging and neurodegenerative disorders?

“…Altered miRNA expression and disruption of miRNA biogenesis through deletion of the enzyme Dicer, (expression of which declines with age,) can also shift cells into a senescent state (Mori et al, 2012). miRNAs such as miR-29 have been discovered to be master regulators of CS (Hu et al, 2014) and it is possible that individual CS phenotypes such as SASP may also be regulated by specific miRNAs. In C. elegans and Drosophila perturbed miRNA expression can alter lifespan, modulate lipofuscin accumulation in tissues, accelerate a transcriptional profile associated with aging and reduce age-related neurodegeneration (Boehm and Slack, 2005; Liu et al, 2012).…”

Geroconversion: irreversible step to cellular senescence

“…Indeed, aging is not just cell cycle arrest. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] In analogy, although cell cycle progression is important in carcinogenesis, we do not define cancer as cell cycle progression. For one, intestinal and bone marrow progenitor cells proliferate faster than tumor cells.…”