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Updated: Oct 10, 2025
Evaluation of Injury-induced Senescence and In Vivo Reprogramming in the Skeletal Muscle
Published on: October 26, 2017
Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice
Cory M Dungan1,2,3, Kevin A Murach1,3, Christopher J Zdunek3
1Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA.
Abstract:
Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole-body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7- or 28 days prior to euthanization. Senescence-associated β-Galactosidase positive (SA β-Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β-Gal+ cells were also CD11b+ in young and old mice 7- and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β-Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti-inflammatory macrophages. SA β-Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q-treated old mice, muscle regenerated following injury to a greater extent compared to vehicle-treated old mice, having larger fiber cross-sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice.
Insights
Senolytic drugs, dasatinib and quercetin, improved muscle regeneration in old mice but impaired it in young mice. This suggests senolytics enhance repair in aged tissues by targeting specific cellular processes.
Area of Science:
- Gerontology
- Regenerative Medicine
- Skeletal Muscle Biology
Background:
- Senescent cells accumulate with age and contribute to age-related diseases.
- The role of senescent cells in tissue repair, particularly in skeletal muscle, is not fully understood.
- Senolytic drugs aim to clear senescent cells, but their impact on age-related tissue regeneration requires investigation.
Purpose of the Study:
- To investigate the effect of senolytic drugs (dasatinib and quercetin) on skeletal muscle regeneration in young and old mice.
- To determine if senolytics can enhance the repair of aged skeletal muscle following injury.
- To explore the cellular mechanisms underlying the effects of senolytics on muscle regeneration.
Main Methods:
- Young and old mice were treated with dasatinib and quercetin (D+Q) or vehicle for 4 months.
- Skeletal muscle injury was induced using barium chloride (BaCl2) in the tibialis anterior muscle.
- Senescence markers (SA β-Gal+ cells), immune cell infiltration (CD11b+ cells), gene expression, and muscle fiber regeneration were analyzed at different time points post-injury.
- In vitro experiments assessed the effect of D+Q on myogenic progenitor cell proliferation.
Main Results:
- Senescence markers (SA β-Gal+ cells) increased post-injury in both age groups, with senescent cells persisting longer in old mice.
- D+Q treatment reduced senescent cells in old mice but not in young mice.
- Old mice treated with D+Q showed enhanced muscle regeneration, evidenced by larger fiber cross-sectional areas 28 days post-injury.
- Conversely, D+Q treatment impaired muscle regeneration in young mice.
- In vitro studies indicated D+Q directly promote myogenic progenitor cell proliferation.
Conclusions:
- Senolytic treatment with dasatinib and quercetin promotes skeletal muscle regeneration in aged mice.
- The beneficial effects of senolytics on muscle repair are age-dependent, enhancing regeneration in old but impairing it in young mice.
- Senolytics may represent a therapeutic strategy for improving age-related muscle degeneration, but their use requires careful consideration of age-specific effects.
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