Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration
Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration
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DOI：
10.1096/fj.09-146308
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发表时间：
2010-05-01
期刊：
影响因子：
4.8
通讯作者：
Van Remmen, Holly
中科院分区：
文献类型：
--
作者：
Jang, Youngmok C.;Lustgarten, Michael S.;Van Remmen, Holly
氧化应激与年龄相关性肌肉萎缩(骨质疏松症)的病因学有关。然而，氧化应激导致石棺减少的潜在机制还没有得到彻底的研究。为了直接研究慢性氧化应激在体内的作用，我们使用了一个缺乏抗氧化酶CuZnSOD(SOD1)的小鼠模型。SOD1(-/-)小鼠的特点是高水平的氧化损伤和加速的石棺减少。在目前的研究中，我们证明了SOD1(-/-)小鼠的肌肉萎缩伴随着线粒体生物能量功能的进行性下降和线粒体产生的活性氧物种的增加。此外，SOD1(-/-)肌肉表现出更快地诱导线粒体介导的细胞凋亡和肌核丢失。此外，老年SOD1(-/-)小鼠神经肌肉接头(NMJ)附近的肌肉线粒体含量显著增加。尽管含量增加，但线粒体的功能明显受损，失神经NMJ增加，乙酰胆碱受体碎裂。其结果是，老年SOD(-/-)肌肉的收缩力量大大减弱。总之，我们发现SOD1(-/-)小鼠以加速的方式表现出正常衰老肌肉的特征，并提出超氧化物诱导的NMJ退化和线粒体功能障碍是骨质疏松症的潜在机制。-Jang，Y.C.，Lustgarten，M.S.，Liu，Y.，Muller，F.L.，Bhattacharya，A.，Leung，H.，Salmon，A.B.，Brooks，S.V.，Larkin，L.，Hayworth，C.R.，Richardson，A.，和Van Remman，H.体内增加的超氧化物通过线粒体功能障碍和神经肌肉连接退化加速与年龄相关的肌肉萎缩。FASE B J.24,1376-1390(2010)。Www.fasebj.org
Oxidative stress has been implicated in the etiology of age-related muscle loss (sarcopenia). However, the underlying mechanisms by which oxidative stress contributes to sarcopenia have not been thoroughly investigated. To directly examine the role of chronic oxidative stress in vivo, we used a mouse model that lacks the antioxidant enzyme CuZnSOD (Sod1). Sod1(-/-) mice are characterized by high levels of oxidative damage and an acceleration of sarcopenia. In the present study, we demonstrate that muscle atrophy in Sod1(-/-) mice is accompanied by a progressive decline in mitochondrial bioenergetic function and an elevation of mitochondrial generation of reactive oxygen species. In addition, Sod1(-/-) muscle exhibits a more rapid induction of mitochondrial-mediated apoptosis and loss of myonuclei. Furthermore, aged Sod1(-/-) mice show a striking increase in muscle mitochondrial content near the neuromuscular junctions (NMJs). Despite the increase in content, the function of mitochondria is significantly impaired, with increased denervated NMJs and fragmentation of acetylcholine receptors. As a consequence, contractile force in aged Sod1(-/-) muscles is greatly diminished. Collectively, we show that Sod1(-/-) mice display characteristics of normal aging muscle in an accelerated manner and propose that the superoxide-induced NMJ degeneration and mitochondrial dysfunction are potential mechanisms of sarcopenia.-Jang, Y. C., Lustgarten, M. S., Liu, Y., Muller, F. L., Bhattacharya, A., Liang, H., Salmon, A. B., Brooks, S. V., Larkin, L., Hayworth, C. R., Richardson, A., and Van Remmen, H. Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration. FASEB J. 24, 1376-1390 (2010). www.fasebj.org