Inhibition of p53-MDM2 binding reduces senescent cell abundance and improves the adaptive responses of skeletal muscle from aged mice.

Autor: Nolt GL; Department of Physiology, University of Kentucky, Lexington, KY, USA.; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA., Keeble AR; Department of Physiology, University of Kentucky, Lexington, KY, USA.; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA., Wen Y; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Department of Physical Therapy, University of Kentucky, Lexington, KY, USA., Strong AC; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA., Thomas NT; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, USA., Valentino TR; Department of Physiology, University of Kentucky, Lexington, KY, USA.; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA., Brightwell CR; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, USA., Murach KA; Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, USA., Patrizia S; Regenerative Medicine, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Weinstabl H; Boehringer Ingelheim RCV, Boehringer Ingelheim Pharmaceuticals Inc., Vienna, Austria., Gollner A; Boehringer Ingelheim RCV, Boehringer Ingelheim Pharmaceuticals Inc., Vienna, Austria., McCarthy JJ; Department of Physiology, University of Kentucky, Lexington, KY, USA.; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA., Fry CS; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, USA., Franti M; Regenerative Medicine, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA., Filareto A; Regenerative Medicine, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA. antonio.filareto@boehringer-ingelheim.com., Peterson CA; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.; Department of Physical Therapy, University of Kentucky, Lexington, KY, USA., Dungan CM; The Center for Muscle Biology, University of Kentucky, Lexington, KY, USA. Cory_Dungan@baylor.edu.; Department of Physical Therapy, University of Kentucky, Lexington, KY, USA. Cory_Dungan@baylor.edu.; Department of Health, Human Performance, and Recreation, Baylor University, One Bear Place #97313, Waco, TX, 76706, USA. Cory_Dungan@baylor.edu.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2024 Apr; Vol. 46 (2), pp. 2153-2176. Date of Electronic Publication: 2023 Oct 24.
DOI: 10.1007/s11357-023-00976-2
Abstrakt: Skeletal muscle adaptation to external stimuli, such as regeneration following injury and hypertrophy in response to resistance exercise, are blunted with advanced age. The accumulation of senescent cells, along with defects in myogenic progenitor cell (MPC) proliferation, have been strongly linked as contributing factors to age-associated impairment in muscle adaptation. p53 plays an integral role in all these processes, as upregulation of p53 causes apoptosis in senescent cells and prevents mitotic catastrophe in MPCs from old mice. The goal of this study was to determine if a novel pharmaceutical agent (BI01), which functions by upregulating p53 through inhibition of binding to MDM2, the primary p53 regulatory protein, improves muscle regeneration and hypertrophy in old mice. BI01 effectively reduced the number of senescent cells in vitro but had no effect on MPC survival or proliferation at a comparable dose. Following repeated oral gavage with 2 mg/kg of BI01 (OS) or vehicle (OV), old mice (24 months) underwent unilateral BaCl 2 injury in the tibialis anterior (TA) muscle, with PBS injections serving as controls. After 7 days, satellite cell number was higher in the TA of OS compared to OV mice, as was the expression of genes involved in ATP production. By 35 days, old mice treated with BI01 displayed reduced senescent cell burden, enhanced regeneration (higher muscle mass and fiber cross-sectional area) and restoration of muscle function relative to OV mice. To examine the impact of 2 mg/kg BI01 on muscle hypertrophy, the plantaris muscle was subjected to 28 days of mechanical overload (MOV) in OS and OV mice. In response to MOV, OS mice had larger plantaris muscles and muscle fibers than OV mice, particularly type 2b + x fibers, associated with reduced senescent cells. Together our data show that BI01 is an effective senolytic agent that may also augment muscle metabolism to enhance muscle regeneration and hypertrophy in old mice.
(© 2023. The Author(s).)
Databáze: MEDLINE
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