Senescent Cells in Muscle Tissue Harm Muscle Stem Cell Function
Researchers here use fisetin as a senolytic in progeroid mice to demonstrate that senescent cells in muscle tissue are harmful to tissue function via a negative impact on muscle stem cells. Mice with this form of progeroid mutation generate a lot of senescent cells, far more than occurs during normal aging, but the principle may nonetheless hold, that senescent cells are providing a meaningful contribution to age-related loss of muscle mass and strength. The proof lies in running the studies.
Muscle progenitor/stem cells (MPCs) progressively lose their capacity for proliferation and myogenic differentiation during the ageing process, likely through both autonomous and non-autonomous mechanisms. The cell autonomous mechanism mainly involves increased DNA damage, telomere shortening, and activation of chronic inflammatory signalling (i.e. NF-κB), whereas the cell non-autonomous mechanism involves the regulatory roles of other types of neighbouring cells in the tissues on the function of local stem cells. However, the mechanism of MPCs being regulated by neighbouring cells during the ageing process of muscles remains largely unknown.
Adjacent to MPCs in the skeletal muscle are myofibres, immune cells, blood vessel endothelial cells and fibro-adipogenic progenitors (FAPs). FAPs are tissue-resident mesenchymal stromal cells (MSCs) characterized by the high expression of PDGFR-α that play important roles in the homeostasis and repair of multiple tissues. By studying the muscles and primary cells of age matched wild-type (WT) mice and Zmpste24-/- (Z24-/-) mice, an accelerated ageing model for Hutchinson-Gilford progeria syndrome (HGPS), we examined the interaction between FAPs and MPCs in progeria-aged muscle, and the potential effect of senolytic drug fisetin in removing senescent FAPs and improving the function of MPCs.
We observed that, compared with muscles of WT mice, muscles of Z24-/- mice contained a significantly increased number of FAPs (2.4-fold) and decreased number of MPCs (2.8-fold). FAPs isolated from Z24-/- muscle contained about 44% SA-β-gal+ senescent cells, in contrast to about 3.5% senescent cells in FAPs isolated from WT muscle. The treatment of the in vitro co-culture system of Z24-/- FAPs and WT MPCs with the senolytic drug fisetin led to increased apoptosis of Z24-/- FAPs (14.5-fold) and rescued the impaired function of MPCs by increasing the number of MHC-positive myotubes for 3.1 times. Treatment of Z24-/- mice with fisetin in vivo was effective in reducing the number of senescent FAPs and restoring the number of muscle stem cells (2.6-fold), leading to improved muscle pathology in Z24-/- mice.
These results indicate that the application of senolytics in the progeria-aged muscles can be an efficient strategy to remove senescent cells, including senescent FAPs, which results in improved function of muscle progenitor/stem cells. The senescent FAPs can be a potential novel target for therapeutic treatment of progeria ageing related muscle diseases.