Muscle-derived miR-34a increases with age in circulating extracellular vesicles and induces senescence of bone marrow stem cells

Sadanand T Fulzele, Bharati Mendhe, Andrew Khayrullin, Maribeth H Johnson, Helen Kaiser, Yutao Liu, Carlos M Isales, Mark W Hamrick

Research output: Contribution to journalArticle

Abstract

Extracellular vesicles (EVs) are known to play important roles in cell-cell communication. Here we investigated the role of muscle-derived EVs and their microRNAs in the loss of bone stem cell populations with age. Aging in male and female C57BL6 mice was associated with a significant increase in expression of the senescenceassociated microRNA miR-34a-5p (miR-34a) in skeletal muscle and in serum -derived EVs. Muscle-derived, alpha-sarcoglycan positive, EVs isolated from serum samples also showed a significant increase in miR-34a with age. EVs were isolated from conditioned medium of C2C12 mouse myoblasts and primary human myotubes after cells were treated with hydrogen peroxide to simulate oxidative stress. These EVs were shown to have elevated levels of miR-34a, and these EVs decreased viability of bone marrow mesenchymal (stromal) cells (BMSCs) and increased BMSC senescence. A lentiviral vector system was used to overexpress miR-34a in C2C12 cells, and EVs isolated from these transfected cells were observed to home to bone in vivo and to induce senescence and decrease Sirt1 expression of primary bone marrow cells ex vivo. These findings suggest that aged skeletal muscle is a potential source of circulating, senescence-associated EVs that may directly impact stem cell populations in tissues such as bone via their microRNA cargo.

Original languageEnglish (US)
Pages (from-to)1791-1803
Number of pages13
JournalAging
Volume11
Issue number6
DOIs
StatePublished - Mar 31 2019

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Bone Marrow Cells
Stem Cells
Muscles
Mesenchymal Stromal Cells
MicroRNAs
Bone and Bones
Skeletal Muscle
Sarcoglycans
Extracellular Vesicles
Myoblasts
Cell Aging
Skeletal Muscle Fibers
Conditioned Culture Medium
Serum
Cell Communication
Hydrogen Peroxide
Population
Oxidative Stress

Keywords

  • Exosomes
  • Muscle-bone crosstalk
  • Osteoporosis
  • Sarcopenia
  • Senescence

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Muscle-derived miR-34a increases with age in circulating extracellular vesicles and induces senescence of bone marrow stem cells. / Fulzele, Sadanand T; Mendhe, Bharati; Khayrullin, Andrew; Johnson, Maribeth H; Kaiser, Helen; Liu, Yutao; Isales, Carlos M; Hamrick, Mark W.

In: Aging, Vol. 11, No. 6, 31.03.2019, p. 1791-1803.

Research output: Contribution to journalArticle

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