ALDH2 Mutation Promotes Skeletal Muscle Atrophy in Mice Via Accumulation of Oxidative Stress.
Bone(2021)
摘要
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 auto-phagosome 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.
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关键词
Muscle atrophy,ALDH2,Oxidative stress
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