Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells.
Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells.
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DOI：
10.1016/j.freeradbiomed.2014.02.023
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发表时间：
2014-06
影响因子：
7.4
通讯作者：
Rajasekaran, Namakkal S.
中科院分区：
文献类型：
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作者：
Narasimhan, Madhusudhanan;Hong, Jennifer;Atieno, Nancy;Muthusamy, Vasanthi R.;Davidson, Christopher J.;Abu-Rmaileh, Naser;Richardson, Russell S.;Gomes, Aldrin V.;Hoidal, John R.;Rajasekaran, Namakkal S.
骨骼肌氧化还原稳态受核红细胞 2-p45 相关因子 2 (Nrf2) 的转录调节。我们最近证明，与年龄相关的压力会损害 Nrf2-ARE（抗氧化反应元件）转录信号。在这里，我们假设 Nrf2 的年龄依赖性衰退或基因消除会导致加速细胞凋亡和骨骼肌退化。在基础生理条件下，Nrf2 的破坏会显着下调抗氧化剂并引起氧化应激。令人惊讶的是，在急性耐力运动应激（AEES）下，Nrf2缺失小鼠的抗氧化能力与野生型（WT）相同，这表明激活了Nrf2独立机制（即PGC1α）对抗氧化应激。对基础状态下促生存途径的分析显示，与 WT 小鼠相比，Nrf2-null 小鼠中 Akt 水平降低，而 Akt 抑制因子 pp53 升高。与 WT 骨骼肌相比，AEES 后，Nrf2-null 骨骼肌中 Akt 和 p-Akt 水平显着（p<0.001）增加（>10 倍），同时 pp53 深度下调（p<0.01），表明促生存机制的开始，以补偿 Nrf2 信号传导的损失。然而，我们发现，与 WT 小鼠相比，AEES 处理后 Nrf2-null 小鼠的干细胞数量 (Pax7) 和 MyoD 表达（分化）减少，并且泛素和凋亡途径深度激活，这表明补偿性促生存机制未能克服骨骼肌中的程序性细胞死亡和退化。此外，在 AEES 恢复 1 周后，与 WT 小鼠相比，Nrf2 缺失小鼠的再生受损持续存在。在与年龄相关的氧化应激条件下，Nrf2 的消除会导致细胞凋亡的诱导和肌肉再生受损。
Skeletal muscle redox homoeostasis is transcriptionally regulated by nuclear erythroid-2-p45-related factor-2 (Nrf2). We recently demonstrated that age-associated stress impairs Nrf2-ARE (antioxidant response element) transcriptional signaling. Here, we hypothesize that age-dependent decline or genetic ablation of Nrf2 leads to accelerated apoptosis and skeletal muscle degeneration. Under basal-physiological conditions, disruption of Nrf2 significantly down regulates antioxidants and causes oxidative stress. Surprisingly, Nrf2-null mice had enhanced antioxidant capacity identical to wild-type (WT) upon acute endurance exercise stress (AEES), suggesting activation of Nrf2-independent mechanisms (i.e. PGC1α) against oxidative stress. Analysis of pro-survival pathways under the basal state reveals decreased Akt levels, while pp53, a repressor of Akt, was increased in Nrf2-null versus WT mice. Upon AEES, Akt and p-Akt levels were significantly (p<0.001) increased (>10 fold) along with profound down regulation of pp53 (p<0.01) in Nrf2-null versus WT skeletal muscle, indicating the onset of pro-survival mechanisms to compensate the loss of Nrf2 signaling. However, we found a decreased stem cell population (Pax7) and MyoD expression (differentiation) along with profound activation of ubiquitin and apoptotic pathways in Nrf2- null versus WT mice upon AEES, suggesting that compensatory pro-survival mechanisms failed to overcome the programed cell death and degeneration in skeletal muscle. Further, the impaired regeneration was sustained in Nrf2-null vs. WT mice after 1 week of post-AEES recovery. In an age-associated oxidative stress condition, ablation of Nrf2 results in induction of apoptosis and impaired muscle regeneration.
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影响因子：
--
作者：
Acharya A;Das I;Chandhok D;Saha T
通讯作者：
Saha T
影响因子：
3.9
作者：
Fulle, S;Di Donna, S;Fanò, G
通讯作者：
Fanò, G
影响因子：
8
作者：
Cao, C;Li, YP;Kufe, D
通讯作者：
Kufe, D
影响因子：
3.9
作者：
Gianni, P;Kaczor, JJ;Tarnopolsky, MA
通讯作者：
Tarnopolsky, MA
DOI：
10.1016/s0735-1097(86)80321-7
发表时间：
1986-12-01
影响因子：
24
作者：
ANVERSA, P;HILER, B;OLIVETTI, G
通讯作者：
OLIVETTI, G