Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice.

Autor: Dungan CM; Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA.; Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.; The Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA., Murach KA; Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA.; The Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA., Zdunek CJ; The Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA., Tang ZJ; Computational Biology, GCBDS, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA., Nolt GL; The Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA., Brightwell CR; The Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA.; Department of Athletic Training and Clinical Nutrition, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA., Hettinger Z; Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA.; The Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA., Englund DA; Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA.; The Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA., Liu Z; Computational Biology, GCBDS, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA., Fry CS; The Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA.; Department of Athletic Training and Clinical Nutrition, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA., Filareto A; Regenerative Medicine, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA., Franti M; Regenerative Medicine, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA., Peterson CA; Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA.; The Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2022 Jan; Vol. 21 (1), pp. e13528. Date of Electronic Publication: 2021 Dec 13.
DOI: 10.1111/acel.13528
Abstrakt: 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% BaCl 2 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.
(© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje