Inhibition of p53-MDM2 binding reduces senescent cell abundance and improves the adaptive responses of skeletal muscle from aged mice.
Inhibition of p53-MDM2 binding reduces senescent cell abundance and improves the adaptive responses of skeletal muscle from aged mice.
复制标题
DOI：
10.1007/s11357-023-00976-2
复制
发表时间：
2024-04
期刊：
影响因子：
5.6
通讯作者：
Dungan, Cory M.
中科院分区：
文献类型：
--
作者：
Nolt, Georgia L.;Keeble, Alexander R.;Wen, Yuan;Strong, Aubrey C.;Thomas, Nicholas T.;Valentino, Taylor R.;Brightwell, Camille R.;Murach, Kevin A.;Patrizia, Sini;Weinstabl, Harald;Gollner, Andreas;Mccarthy, John J.;Fry, Christopher S.;Franti, Michael;Filareto, Antonio;Peterson, Charlotte A.;Dungan, Cory M.
骨骼肌对外界刺激的适应性，如损伤后的再生和抵抗运动反应的肥大，随着年龄的增加而变得迟钝。衰老细胞的积累，以及成肌祖细胞(MPC)增殖的缺陷，已经被强烈地联系在一起，作为与年龄相关的肌肉适应障碍的因素。P53在所有这些过程中发挥着不可或缺的作用，因为P53的上调导致衰老细胞的凋亡，并防止老年小鼠的MPC发生有丝分裂灾难。这项研究的目的是确定一种新的药物制剂(BI01)是否可以改善老年小鼠的肌肉再生和肥大。BI01通过抑制与主要的p53调节蛋白MDM2的结合来上调p53的功能。BI01有效地减少了体外衰老细胞的数量，但在同等剂量下对MPC的存活或增殖没有影响。老年小鼠(24月龄)连续灌胃BI01(OS)或赋形剂(OV)2 mg/kg，造成单侧胫前肌BaCl2损伤，以PBS注射为对照。7天后，OS小鼠TA的卫星细胞数高于OV小鼠，参与ATP产生的基因表达也较高。到35天时，与OV小鼠相比，接受BI01治疗的老年小鼠显示出衰老细胞负担减少，再生增强(更高的肌肉质量和纤维横截面积)和肌肉功能恢复。为探讨2 mg/kg BI01对小鼠足底肌肉肥大的影响，对OS和OV小鼠进行了28天的机械超负荷(MOV)实验。在对MOV的反应中，OS小鼠的足底肌肉和肌肉纤维比OV小鼠更大，特别是2b型 + x纤维，与衰老细胞减少相关。总而言之，我们的数据显示BI01是一种有效的感觉剂，也可以增强肌肉代谢，促进老年小鼠肌肉再生和肥大。网上版载有补充材料，可在10.1007/s11357-023-00976-2查阅。
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 BaCl2 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. The online version contains supplementary material available at 10.1007/s11357-023-00976-2.
登录
查看更多内容
影响因子：
8.1
作者：
Englund, Davis A.;Jolliffe, Alyssa;Aversa, Zaira;Zhang, Xu;Sturmlechner, Ines;Sakamoto, Ayumi E.;Zeidler, Julianna D.;Warner, Gina M.;McNinch, Colton;White, Thomas A.;Chini, Eduardo N.;Baker, Darren J.;van Deursen, Jan M.;LeBrasseur, Nathan K.
通讯作者：
LeBrasseur, Nathan K.
卫星细胞耗竭会破坏转录协调和肌肉适应运动。
DOI：
10.1093/function/zqaa033
发表时间：
2021
期刊：
Function (Oxford, England)
影响因子：
--
作者：
Englund DA;Figueiredo VC;Dungan CM;Murach KA;Peck BD;Petrosino JM;Brightwell CR;Dupont AM;Neal AC;Fry CS;Accornero F;McCarthy JJ;Peterson CA
通讯作者：
Peterson CA
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
--
作者：
Goodman CA;Coenen AM;Frey JW;You JS;Barker RG;Frankish BP;Murphy RM;Hornberger TA
通讯作者：
Hornberger TA
影响因子：
16.6
作者：
通讯作者：
--