Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.
Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.
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肌肉炎症和纤维化是废用相关并发症的基础，并可能导致衰老过程中肌肉恢复受损。细胞衰老是炎症、细胞外基质（ECM）重塑和废用后肌肉恢复不良之间的新兴联系。在啮齿类动物中，二甲双胍已被证明可预防细胞衰老/衰老相关分泌表型（SASP）、炎症和纤维化，使其成为一种潜在的实用治疗方案。因此，本研究的目的是在老年人中确定卧床期间二甲双胍单药治疗是否可以减少恢复期间的肌肉纤维化和细胞衰老/SASP。在健康的男性和女性老年人（n = 20; BMI：<30，年龄：60岁+）中进行了一项双臂对照试验，在两周的导入期和5天的卧床休息期间随机接受安慰剂或二甲双胍治疗，随后在7天的恢复期停用二甲双胍。我们发现，二甲双胍治疗的个体在废用过程中I型肌纤维萎缩较少，促炎转录谱减少，恢复过程中肌肉胶原沉积减少。胶原蛋白含量和肌纤维大小对应于整个肌肉细胞衰老和SASP标记物减少。此外，二甲双胍治疗减少了原代肌肉驻留脂肪生成祖细胞（FAP）衰老标志物，并促进成纤维细胞命运向肌成纤维细胞样转变。总之，这些结果表明，二甲双胍预处理可能通过改变骨骼肌和FAP中的细胞衰老和SASP来改善老年人废用后的ECM重塑。在卧床休息前2周和卧床休息5天期间向老年人提供甲氨蝶呤，并在卧床期间停用。在接受二甲双胍治疗的老年人中，急性废用后再给药导致细胞衰老和衰老相关分泌表型（SASP）标志物减少，肌肉成脂祖细胞（FAP）肌成纤维细胞群减少，肌肉纤维化程度降低。
Muscle inflammation and fibrosis underlie disuse‐related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link between inflammation, extracellular matrix (ECM) remodeling and poor muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescent associated secretory phenotype (SASP), inflammation, and fibrosis making it a potentially practical therapeutic solution. Thus, the purpose of this study was to determine in older adults if metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the re‐ambulation period. A two‐arm controlled trial was utilized in healthy male and female older adults (n = 20; BMI: <30, age: 60 years+) randomized into either placebo or metformin treatment during a two‐week run‐in and 5 days of bedrest followed by metformin withdrawal during 7 days of recovery. We found that metformin‐treated individuals had less type‐I myofiber atrophy during disuse, reduced pro‐inflammatory transcriptional profiles, and lower muscle collagen deposition during recovery. Collagen content and myofiber size corresponded to reduced whole muscle cellular senescence and SASP markers. Moreover, metformin treatment reduced primary muscle resident fibro‐adipogenic progenitors (FAPs) senescent markers and promoted a shift in fibroblast fate to be less myofibroblast‐like. Together, these results suggest that metformin pre‐treatment improved ECM remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and in FAPs. Metformin was provided to older adults 2 weeks prior and during 5‐days of bed rest and was withdrawn during re‐ambulation. Re‐ambulation after acute disuse in older adults treated with metformin resulted in decreased markers of cellular senescence and senescence associated secretory phenotype (SASP), a decrease in muscle fibro‐adipogenic progenitor (FAP) myofibroblast populations, and lower muscle fibrosis.
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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.
DOI：
10.1096/fj.202100883r
发表时间：
2021-09
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Petrocelli JJ;Mahmassani ZS;Fix DK;Montgomery JA;Reidy PT;McKenzie AI;de Hart NM;Ferrara PJ;Kelley JJ;Eshima H;Funai K;Drummond MJ
通讯作者：
Drummond MJ
影响因子：
5.6
作者：
通讯作者：
--
影响因子：
5.2
作者：
Petrocelli, Jonathan J.;de Hart, Naomi M. M. P.;Lang, Marisa J.;Yee, Elena M.;Ferrara, Patrick J.;Fix, Dennis K.;Chaix, Amandine;Funai, Katsuhiko;Drummond, Micah J.
通讯作者：
Drummond, Micah J.
影响因子：
20.1
作者：
Cameron AR;Morrison VL;Levin D;Mohan M;Forteath C;Beall C;McNeilly AD;Balfour DJ;Savinko T;Wong AK;Viollet B;Sakamoto K;Fagerholm SC;Foretz M;Lang CC;Rena G
通讯作者：
Rena G