Dobrowolny Gabriella, Aucello Michela, Rizzuto Emanuele, Beccafico Sara, Mammucari Cristina, Boncompagni Simona, Belia Silvia, Wannenes Francesca, Nicoletti Carmine, Del Prete Zaccaria, Rosenthal Nadia, Molinaro Mario, Protasi Feliciano, Fanò Giorgio, Sandri Marco, Musarò Antonio
Institute Pasteur Cenci-Bolognetti, Department of Histology and Medical Embryology, CE-BEMM and IIM, Sapienza University of Rome,Via A. Scarpa, 14 Rome 00161, Italy.
Cell Metab. 2008 Nov;8(5):425-36. doi: 10.1016/j.cmet.2008.09.002.
The antioxidant enzyme superoxide dismutase 1 (SOD1) is a critical player of the antioxidative defense whose activity is altered in several chronic diseases, including amyotrophic lateral sclerosis. However, how oxidative insult affects muscle homeostasis remains unclear. This study addresses the role of oxidative stress on muscle homeostasis and function by the generation of a transgenic mouse model expressing a mutant SOD1 gene (SOD1(G93A)) selectively in skeletal muscle. Transgenic mice developed progressive muscle atrophy, associated with a significant reduction in muscle strength, alterations in the contractile apparatus, and mitochondrial dysfunction. The analysis of molecular pathways associated with muscle atrophy revealed that accumulation of oxidative stress served as signaling molecules to initiate autophagy, one of the major intracellular degradation mechanisms. These data demonstrate that skeletal muscle is a primary target of SOD1(G93A) -mediated toxicity and disclose the molecular mechanism whereby oxidative stress triggers muscle atrophy.
抗氧化酶超氧化物歧化酶1（SOD1）是抗氧化防御的关键参与者，其活性在包括肌萎缩侧索硬化症在内的几种慢性疾病中会发生改变。然而，氧化损伤如何影响肌肉稳态仍不清楚。本研究通过构建在骨骼肌中选择性表达突变型SOD1基因（SOD1(G93A)）的转基因小鼠模型，探讨氧化应激对肌肉稳态和功能的作用。转基因小鼠出现进行性肌肉萎缩，伴有肌肉力量显著降低、收缩装置改变和线粒体功能障碍。对与肌肉萎缩相关分子途径的分析表明，氧化应激的积累作为信号分子启动自噬，自噬是主要的细胞内降解机制之一。这些数据表明骨骼肌是SOD1(G93A)介导毒性的主要靶点，并揭示了氧化应激触发肌肉萎缩的分子机制。
