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

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 senescence-associated 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.

The mechanisms and treatments for sarcopenia: could exosomes be a perspective research strategy in the future?

“…For instance, EVs‐miR‐133b and EVs‐miR‐181a‐5p were observed to be significantly up‐regulated after exercise, which possibly may be related to muscle remodelling and homeostasis . Recently, it has been discovered that muscle‐derived EVs carrying senescence‐associated miRNAs, such as miR‐34a‐5p (miR‐34a), were able to induce cellular senescence in bone stem cells . Exosomes belong to EVs and carry significant information, such as proteins, DNAs, miRNAs, and circular RNAs .…”

Advance in Drug Delivery for Ageing Skeletal Muscle

“…As mentioned above, Fulzele, S. et al. found EVs-derived miR-34a could regulate muscle metabolism ( Fulzele et al., 2019 ). Many studies investigated that physical exercise, which is closely related with muscle regeneration, can induce rapid release of EVs into the blood circulation.…”

“…Zanotti S et al found that EVs derived from local fibroblasts in the Duchenne muscular dystrophy (DMD) muscle are able to induce a transfer of unactivated fibroblasts to myofibroblasts thereby motivating the fibrotic response (Zanotti et al, 2018). As mentioned above, Fulzele, S. et al found EVs-derived miR-34a could regulate muscle metabolism (Fulzele et al, 2019). Many studies investigated that physical exercise, which is closely related with muscle regeneration, can induce rapid release of EVs into the blood circulation.…”

“…found a significant increase in expression of senescence-associated EVs-derived miR-34a in skeletal muscle from ageing mice. The results indicated that senescence‐associated EVs secreted from skeletal muscle may directly reduce stem cell populations via their microRNA cargo ( Fulzele et al., 2019 ). As the growing understanding of EVs, more therapeutic targets may be constantly discovered.…”

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

“…The important role played by EVs in cell-cell communication was involved in the loss of bone stem cell population with age. In particular, skeletal muscle EVs carrying senescence-associated miRNAs (miR-34a) can affect BM-MSC viability, decrease Sirt-1 expression and induce BM-MSC senescence, thus suggesting a role of skeletal muscle in age-related decline of BM-MSCs [177]. Conversely, aged MSCs, showing activated AKT signalling which affects EV RNA profile, produce EVs able to cause aging of HSCs [96].…”