Geriatric Medicine Department, Yantai Yuhuangding Hospital, Yantai 264000, China.
Geriatric Cardiovascular Department, The Affiliated Taian City Central Hospital of Qingdao University, Taian 271000, China.
Exp Gerontol. 2024 Aug;193:112468. doi: 10.1016/j.exger.2024.112468. Epub 2024 May 28.
BACKGROUND: Aged sarcopenia is characterized by loss of skeletal muscle mass and strength, and mitochondrial dysregulation in skeletal myocyte is considered as a major factor. Here, we aimed to analyze the effects of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) on mitochondrial reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) in aged skeletal muscles. METHODS: C2C12 cells were stimulated by 50 μM 7β-hydroxycholesterol (7β-OHC) to observe the changes of cellular ROS, mitochondrial ROS, and expression of PGC-1α and Nrf2. Different PGC-1α expression in cells was established by transfection with small interfering RNA (siRNA) or plasmids overexpressing PGC-1α (pEX-3-PGC-1α). The effects of different PGC-1α expression on cellular ROS, mitochondrial ROS and Nrf2 expression were measured in cells. Wild type (WT) mice and PGC-1α conditional knockout (CKO) mice were used to analyze the effects of PGC-1α on aged sarcopenia and expression of Nrf2 and CD38 in gastrocnemius muscles. Diethylmaleate, a Nrf2 activator, was used to analyze the connection between PGC-1α and Nrf2 in cells and in mice. RESULTS: In C2C12 cells, the expressions of PGC-1α and Nrf2 were declined by the 7β-OHC treatment or PGC-1α silence. Moreover, PGC-1α silence increased the harmful ROS and decreased the Nrf2 protein expression in the 7β-OHC-treated cells. PGC-1α overexpression decreased the harmful ROS and increased the Nrf2 protein expression in the 7β-OHC-treated cells. Diethylmaleate treatment decreased the harmful ROS in the 7β-OHC-treated or PGC-1α siRNA-transfected cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia, decreased Nrf2 expression and increased CD38 expression in gastrocnemius muscles compared with the WT mice. Diethylmaleate treatment improved the muscle function and decreased the CD38 expression in the old two genotypes. CONCLUSIONS: Our study demonstrated that PGC-1α modulated mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.
背景：衰老性肌肉减少症的特征是骨骼肌质量和力量的丧失，以及骨骼肌细胞中线粒体的失调，被认为是一个主要因素。在这里，我们旨在分析过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）对衰老骨骼肌中线粒体活性氧（ROS）和核因子红细胞 2 相关因子 2（Nrf2）的影响。
方法：用 50 μM 7β-羟胆固醇（7β-OHC）刺激 C2C12 细胞，观察细胞 ROS、线粒体 ROS 和 PGC-1α和 Nrf2 的表达变化。用小干扰 RNA（siRNA）或过表达 PGC-1α的质粒（pEX-3-PGC-1α）转染建立不同的 PGC-1α表达细胞。测量不同 PGC-1α表达对细胞 ROS、线粒体 ROS 和 Nrf2 表达的影响。使用野生型（WT）小鼠和 PGC-1α条件性敲除（CKO）小鼠分析 PGC-1α对衰老性肌肉减少症和腓肠肌中 Nrf2 和 CD38 表达的影响。使用 Nrf2 激活剂二乙基马来酸分析细胞和小鼠中 PGC-1α和 Nrf2 之间的联系。
结果：在 C2C12 细胞中，7β-OHC 处理或 PGC-1α 沉默降低了 PGC-1α和 Nrf2 的表达。此外，PGC-1α 沉默增加了 7β-OHC 处理细胞中的有害 ROS，并降低了 Nrf2 蛋白表达。PGC-1α 过表达降低了 7β-OHC 处理细胞中的有害 ROS，并增加了 Nrf2 蛋白表达。二乙基马来酸处理降低了 7β-OHC 处理或 PGC-1α siRNA 转染细胞中的有害 ROS。在相同的年龄，与 WT 小鼠相比，肌肉特异性 PGC-1α 缺乏加重了衰老性肌肉减少症，降低了腓肠肌中的 Nrf2 表达并增加了 CD38 的表达。二乙基马来酸处理改善了两种老年基因型的肌肉功能并降低了 CD38 的表达。
结论：我们的研究表明，PGC-1α 通过调节 Nrf2 调节衰老性肌肉减少症中线粒体氧化应激。
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