Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice.
Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice.
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使用鼻溶液术对SAβ-GAL+细胞的缺失改善了旧小鼠的肌肉再生。
DOI：
10.1111/acel.13528
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发表时间：
2022-01
期刊：
影响因子：
7.8
通讯作者：
Peterson CA
中科院分区：
文献类型：
--
作者：
Dungan CM;Murach KA;Zdunek CJ;Tang ZJ;Nolt GL;Brightwell CR;Hettinger Z;Englund DA;Liu Z;Fry CS;Filareto A;Franti M;Peterson CA
衰老细胞的系统性缺失导致认知、心血管和全身代谢的稳健改善，但它们在组织修复过程中的作用尚不完全清楚。我们假设，衰老清除药物将促进再生，在老年骨骼肌。年轻（3个月）和老年（20个月）雄性C57 Bl/6 J小鼠每两周给予senolytics达沙替尼（5 mg/kg）和槲皮素（50 mg/kg）或溶媒，持续4个月。然后在安乐死前7天或28天向胫骨前肌（TA）注射1.2% BaCl 2或PBS。在年轻和老年小鼠的肌肉中，衰老相关β-半乳糖苷酶阳性（SA β-Gal+）细胞丰度较低，并且在两个年龄组中损伤后7天相似地增加，D+Q没有影响。大多数SA β-Gal+细胞在损伤后7天和14天的年轻和老年小鼠中也是CD 11b+，表明它们是浸润性免疫细胞。到第14天，来自老年小鼠的SA β-Gal+/CD 11b+细胞表达衰老基因，而来自年轻小鼠的SA β-Gal+/CD 11b+细胞表达更高水平的抗炎巨噬细胞特征基因。与损伤后28天的年轻小鼠相比，老年小鼠中的SA β-Gal+细胞仍然升高，仅在老年小鼠中D+Q降低。在D+Q处理的老年小鼠中，与溶剂处理的老年小鼠相比，损伤后肌肉再生的程度更大，28天后具有更大的纤维横截面积。相反，D+Q使年轻小鼠的再生钝化。体外实验提示D+Q可直接促进肌源性祖细胞增殖。增强的身体功能和改善的肌肉再生表明，senolytics仅在老年小鼠中具有有益效果。Senolytics改善老年小鼠的肌肉再生，而对年轻小鼠没有任何好处。相对于未治疗的老年小鼠，老年小鼠显示出更多的卫星细胞，减少的炎症，较低的衰老细胞负荷，以及生物能量途径的基因表达增加。
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. Senolytics improve muscle regeneration in old mice, while providing no benefit in young mice. Old mice display more satellite cells, reduced inflammation, a lower senescent cell burden, and increased gene expression of bioenergetic pathways relative to untreated old mice.
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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
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
29
作者：
Egerman MA;Cadena SM;Gilbert JA;Meyer A;Nelson HN;Swalley SE;Mallozzi C;Jacobi C;Jennings LL;Clay I;Laurent G;Ma S;Brachat S;Lach-Trifilieff E;Shavlakadze T;Trendelenburg AU;Brack AS;Glass DJ
通讯作者：
Glass DJ
影响因子：
16.6
作者：
Du H;Shih CH;Wosczyna MN;Mueller AA;Cho J;Aggarwal A;Rando TA;Feldman BJ
通讯作者：
Feldman BJ
影响因子：
11.8
作者：
Demaria, Marco;Ohtani, Naoko;Youssef, Sameh A.;Rodier, Francis;Toussaint, Wendy;Mitchell, James R.;Laberge, Remi-Martin;Vijg, Jan;Van Steeg, Harry;Dolle, Martijn E. T.;Hoeijmakers, Jan H. J.;de Bruin, Alain;Hara, Eiji;Campisi, Judith
通讯作者：
Campisi, Judith