磷脂过氧化氢谷胱甘肽过氧化物酶
GPX4
内分泌学
内科学
肌肉萎缩
骨骼肌
去神经支配
脂质过氧化
谷胱甘肽过氧化物酶
萎缩
化学
肌萎缩
谷胱甘肽
生物
生物化学
超氧化物歧化酶
氧化应激
医学
酶
作者
Agnieszka Czyżowska,Jacob L. Brown,Hongyang Xu,Kavitha Sataranatarajan,Michael Kinter,Victoria J. Tyrell,Valerie B. O’Donnell,Holly Van Remmen
出处
期刊:Redox biology
[Elsevier]
日期:2023-06-01
卷期号:64: 102761-102761
被引量:10
标识
DOI:10.1016/j.redox.2023.102761
摘要
Our previous studies support a key role for mitochondrial lipid hydroperoxides as important contributors to denervation-related muscle atrophy, including muscle atrophy associated with aging. Phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that directly reduces phospholipid hydroperoxides and we previously reported that denervation-induced muscle atrophy is blunted in a mouse model of GPX4 overexpression. Therefore, the goal of the present study was to determine whether GPX4 overexpression can reduce the age-related increase in mitochondrial hydroperoxides in skeletal muscle and ameliorate age-related muscle atrophy and weakness (sarcopenia). Male C57Bl6 WT and GPX4 transgenic (GPX4Tg) mice were studied at 3 to 5 and 23–29 months of age. Basal mitochondrial peroxide generation was reduced by 34% in muscle fibers from aged GPX4Tg compared to old WT mice. GPX4 overexpression also reduced levels of lipid peroxidation products: 4-HNE, MDA, and LOOHs by 38%, 32%, and 84% respectively in aged GPX4Tg mice compared to aged WT mice. Muscle mass was preserved in old GPX4 Tg mice by 11% and specific force generation was 21% higher in old GPX4Tg versus age matched male WT mice. Oxylipins from lipoxygenases (LOX) and cyclooxygenase (COX), as well as less abundant non-enzymatically generated isomers, were significantly reduced by GPX4 overexpression. The expression of cPLA2, 12/15-LOX and COX-2 were 1.9-, 10.5- and 3.4-fold greater in old versus young WT muscle respectively, and 12/15-LOX and COX-2 levels were reduced by 37% and 35%, respectively in muscle from old GPX4Tg mice. Our study suggests that lipid peroxidation products may play an important role in the development of sarcopenia, and their detoxification might be an effective intervention in preventing muscle atrophy.
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