ALDH2 mutation promotes skeletal muscle atrophy in mice via accumulation of oxidative stress
ALDH2 mutation promotes skeletal muscle atrophy in mice via accumulation of oxidative stress
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DOI：
10.1016/j.bone.2020.115739
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发表时间：
2021-01-01
期刊：
影响因子：
4.1
通讯作者：
Miyamoto, Takeshi
中科院分区：
文献类型：
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作者：
Kobayashi, Hiroki;Nakamura, Satoshi;Miyamoto, Takeshi
肌肉萎缩是由各种因素，包括老化，固定，卸载和使用药物，如类固醇。然而，肌肉萎缩的遗传风险因素鲜为人知。在这里，我们表明，在ALDH 2基因，rs671（ALDH 2 *2），一个显性负突变的错义SNP，促进显着的肌肉萎缩ALDH 2 *2小鼠模型，伴随着合成代谢和分解代谢肌肉因子的表达减少和收购的低营业额状态。我们还证明，自噬期间自噬体形成所需的LC 3的表达在ALDH 2 *2小鼠肌肉中增加。我们发现，4-羟基壬烯醛（4 HNE），过氧化脂质蛋白和氧化剂，积累在ALDH 2 *2小鼠肌肉。我们已经证明rs671突变与酒精代谢物乙醛的血清水平升高有关。我们发现，在乙醛处理后，肌原性细胞中Atrogin 1和MuRF 1的表达显著增加，这一结果在体外被抗氧化剂Trolox C显著抑制。ALDH 2 *2小鼠中的肌肉萎缩也通过饮食给予抗氧化剂维生素E而显著地得到挽救，所述抗氧化剂维生素E阻断4 HNE在肌肉中的积累。综上所述，我们的数据表明，rs671是肌肉萎缩的遗传风险因素，但这种萎缩可以通过维生素E治疗来挽救。
Muscle atrophy is promoted by various factors including aging, immobilization, unloading and use of drugs such as steroids. However, genetic risk factors for muscle atrophy are less well known. Here, we show that a missense SNP in the ALDH2 gene, rs671 (ALDH2*2), a dominant negative mutation, promotes significant muscle atrophy in the ALDH2*2 mouse model, accompanied by decreased expression of anabolic and catabolic muscle factors and acquisition of a low turnover state. We also demonstrate that expression of LC3, which is require for autophagosome formation during autophagy, increases in ALDH2*2 mouse muscles. We show that 4-hydroxynonenal (4HNE), a peroxidated lipid-protein and oxidant, accumulates in ALDH2*2 mouse muscles. We have shown that the rs671 mutation is associated with increased serum levels of acetaldehyde, an alcohol metabolite. We show that expression of the atrogenes Atrogin1 and MuRF1 significantly increased in myogenic cells following acetaldehyde treatment, an outcome significantly inhibited in vitro by Trolox C, an anti-oxidant. Muscle atrophy in ALDH2*2 mice was also significantly rescued by dietary administration of the anti-oxidant vitamin E, which blocked 4HNE accumulation in muscle. Taken together, our data indicate that rs671 is a genetic risk factor for muscle atrophy, but that such atrophy can be rescued by vitamin E treatment.