Long-term detraining reverses the improvement of lifelong exercise on skeletal muscle ferroptosis and inflammation in aging rats: fiber-type dependence of the Keap1/Nrf2 pathway
Long-term detraining reverses the improvement of lifelong exercise on skeletal muscle ferroptosis and inflammation in aging rats: fiber-type dependence of the Keap1/Nrf2 pathway
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DOI：
10.1007/s10522-023-10042-1
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发表时间：
2023-06-08
期刊：
影响因子：
4.5
通讯作者：
Li，Fang-Hui
中科院分区：
文献类型：
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作者：
Wang，Zhuang-Zhi;Xu，Hai-Chen;Li，Fang-Hui
我们研究了终身有氧运动和10个月有氧训练后停训8个月对老龄大鼠循环、骨骼肌氧化应激和炎症的影响。将Sprague-Dawley大鼠随机分为对照组（CON）、停训组（DET）和终身有氧训练组（LAT）。DET组和LAT组分别于8月龄开始有氧跑台运动，18月龄和26月龄停止运动，26月龄处死大鼠。与CON组相比，LAT组血清和骨骼肌中4-羟基壬烯醛（4-HNE）和8-羟基脱氧鸟苷（8-OHdG）含量显著降低。LAT组骨骼肌中超氧化物歧化酶2（SOD 2）水平高于CON组。与LAT相比，DET显著降低骨骼肌中SOD 2蛋白表达和含量，升高丙二醛（MDA）水平。与LAT组相比，DET组脂联素水平显著降低，肿瘤坏死因子α（TNF-α）表达显著升高，磷脂酰肌醇3-激酶（PI 3 K）、蛋白激酶B（AKT）和70 kDa核糖体蛋白S6激酶（P70 S6 K）蛋白表达显著降低，FoxO 1和肌萎缩F盒（MAFbX）蛋白表达显著升高。比目鱼肌中的脂联素和TNF-α表达在组间没有变化，而DET组比目鱼肌中的AKT、哺乳动物雷帕霉素靶蛋白（mTOR）和P70 S6 K的表达低于LAT组。与LAT组相比，DET组股四头肌sestrin 1（SES 1）和核因子红细胞2相关因子2（Nrf 2）蛋白表达降低，而Keap 1 mRNA表达显著上调。有趣的是，各组之间比目鱼肌中SES 1、Nrf 2和Keap 1的蛋白质和mRNA水平没有差异。与对照组相比，LAT显著上调股四头肌和比目鱼肌中铁蛋白重链多肽1（FTH）、谷胱甘肽过氧化物酶4（GPX 4）和溶质载体家族7成员11（SLC 7A 11）蛋白的表达，而与LAT相比，DET下调股四头肌和比目鱼肌中FTH、GPX 4和SLC 7A 11蛋白的表达。在衰老阶段长期停止训练逆转了终身运动对衰老骨骼肌中氧化应激、炎症、铁凋亡和肌肉萎缩的改善作用。股四头肌比比目鱼肌更明显，这可能与Keap 1/Nrf 2通路在不同骨骼肌中的不同变化有关。
We investigated the effects of lifelong aerobic exercise and 8 months of detraining after 10 months of aerobic training on circulation, skeletal muscle oxidative stress, and inflammation in aging rats. Sprague–Dawley rats were randomly assigned to the control (CON), detraining (DET), and lifelong aerobic training (LAT) groups. The DET and LAT groups began aerobic treadmill exercise at the age of 8 months and stopped training at the 18th and 26th month, respectively; all rats were sacrificed when aged 26 months. Compared with CON, LAT remarkably decreased serum and aged skeletal muscle 4-hydroxynonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. Superoxide dismutase 2(SOD2) levels were higher in the LAT group than in the CON group in skeletal muscle. However, DET remarkably decreased SOD2 protein expression and content in the skeletal muscle and increased malondialdehyde (MDA) level compared with LAT. Compared with LAT, DET remarkably downregulated adiponectin and upregulated tumor necrosis factor alpha (TNF-α) expression, while phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and 70-kDa ribosomal protein S6 kinase (P70S6K) protein expression decreased, and that of FoxO1 and muscle atrophy F-box (MAFbX) proteins increased in the quadriceps femoris. Adiponectin and TNF-α expression in the soleus muscle did not change between groups, whereas that of AKT, mammalian target of rapamycin (mTOR), and P70S6K was lower in the soleus in the DET group than in that in the LAT group. Compared with that in the LAT group, sestrin1 (SES1) and nuclear factor erythroid 2–related factor 2 (Nrf2) protein expression in the DET group was lower, whereasKeap1mRNA expression was remarkably upregulated in the quadriceps femoris. Interestingly, the protein and mRNA levels of SES1, Nrf2, and Keap1 in soleus muscle did not differ between groups. LAT remarkably upregulated ferritin heavy polypeptide 1(FTH), glutathione peroxidase 4(GPX4), and solute carrier family 7member 11 (SLC7A11) protein expression in the quadriceps femoris and soleus muscles, compared with CON. However, compared with LAT, DET downregulated FTH, GPX4, and SLC7A11 protein expression in the quadriceps femoris and soleus muscles. Long-term detraining during the aging phase reverses the improvement effect of lifelong exercise on oxidative stress, inflammation, ferroptosis, and muscle atrophy in aging skeletal muscle. The quadriceps femoris is more evident than the soleus, which may be related to the different changes in the Keap1/Nrf2 pathway in different skeletal muscles.