Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production
Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production
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DOI：
10.1152/ajpregu.00767.2006
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发表时间：
2007-09-01
影响因子：
2.8
通讯作者：
Van Remmen, Holly
中科院分区：
文献类型：
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作者：
Muller, Florian L.;Song, Wook;Van Remmen, Holly
活性氧 (ROS)，尤其是线粒体 ROS，被认为在肌肉萎缩中发挥重要作用。我们报告在与肌肉萎缩相关的三种情况下线粒体ROS生成显着增加：衰老、缺乏CuZn-SOD (Sod1(-1-))的小鼠以及神经退行性疾病肌萎缩侧索硬化症(ALS)。 28 至 32 个月大的小鼠肌肉线粒体中 ROS 的生成量比 10 个月大的小鼠高出近三倍，并且与腓肠肌质量减少 30% 相关。在 Sod1(-1-) 小鼠中，与 5 个月大的小鼠相比，20 个月内肌肉线粒体 ROS 产生增加 > 100%，同时肌肉质量损失 > 50%。 ALS G93A 突变小鼠在疾病进展过程中肌肉质量减少 75%，肌肉线粒体 ROS 生成量增加 12 倍。在第二种 ALS 突变模型 H46RH48Q 小鼠中，ROS 产生量大约是对照小鼠的四倍，并且与肌肉质量损失较小（30%）相关。因此，在这些模型中，ROS 的产生与肌肉萎缩的程度密切相关。由于所研究的每种肌肉萎缩模型都在某种程度上与神经支配丧失相关，因此我们有兴趣确定去神经支配是否在手术坐骨神经横断后从后肢肌肉分离的肌肉线粒体中的 ROS 生成中发挥作用。去神经术后 7 天，肌肉线粒体 ROS 产量增加了近 30 倍。我们得出的结论是，线粒体活性氧生成的增强可能是去神经支配引起的萎缩机制中的一个常见因素。
Reactive oxygen species ( ROS), especially mitochondrial ROS, are postulated to play a significant role in muscle atrophy. We report a dramatic increase in mitochondrial ROS generation in three conditions associated with muscle atrophy: in aging, in mice lacking CuZn-SOD ( Sod1(-1-)), and in the neurodegenerative disease, amyotrophic lateral sclerosis ( ALS). ROS generation in muscle mitochondria is nearly threefold higher in 28- to 32-mo-old than in 10-mo-old mice and is associated with a 30% loss in gastrocnemius mass. In Sod1(-1-) mice, muscle mitochondrial ROS production is increased > 100% in 20-mo compared with 5-mo-old mice along with a > 50% loss in muscle mass. ALS G93A mutant mice show a 75% loss of muscle mass during disease progression and up to 12-fold higher muscle mitochondrial ROS generation. In a second ALS mutant model, H46RH48Q mice, ROS production is approximately fourfold higher than in control mice and is associated with a less dramatic loss ( 30%) in muscle mass. Thus ROS production is strongly correlated with the extent of muscle atrophy in these models. Because each of the models of muscle atrophy studied are associated to some degree with a loss of innervation, we were interested in determining whether denervation plays a role in ROS generation in muscle mitochondria isolated from hindlimb muscle following surgical sciatic nerve transection. Seven days postdenervation, muscle mitochondrial ROS production increased nearly 30-fold. We conclude that enhanced generation of mitochondrial ROS may be a common factor in the mechanism underlying denervation-induced atrophy.