The maintenance of skeletal muscle mass depends on the overall balance between the rates of protein synthesis and degradation. Thus, age-related muscle atrophy and function, commonly known as sarcopenia, may result from decreased protein synthesis, increased proteolysis, or simultaneous changes in both processes governed by complex multifactorial mechanisms. Growing evidence implicates oxidative stress and reactive oxygen species (ROS) as an essential regulator of proteolysis. Our previous studies have shown that genetic deletion of CuZn superoxide dismutase (CuZnSOD, Sod1) in mice leads to elevated oxidative stress, muscle atrophy and weakness, and an acceleration in age-related phenotypes associated with sarcopenia. The goal of this study is to determine whether oxidative stress directly influences the acceleration of proteolysis in skeletal muscle of Sod1^−/− mice as a function of age. Compared to control, Sod1^−/− muscle showed a significant elevation in protein carbonyls and 3-nitrotyrosine levels, suggesting high oxidative and nitrosative protein modifications were present. In addition, age-dependent muscle atrophy in Sod1^−/− muscle was accompanied by an upregulation of the cysteine proteases, calpain, and caspase-3, which are known to play a key role in the initial breakdown of sarcomeres during atrophic conditions. Furthermore, an increase in oxidative stress-induced muscle atrophy was also strongly coupled with simultaneous activation of two major proteolytic systems, the ubiquitin-proteasome and lysosomal autophagy pathways. Collectively, our data suggest that chronic oxidative stress in Sod1^−/− mice accelerates age-dependent muscle atrophy by enhancing coordinated activation of the proteolytic systems, thereby resulting in overall protein degradation.

骨骼肌质量的维持取决于蛋白质合成和降解速率之间的整体平衡。因此，与年龄相关的肌肉萎缩和功能，通常称为肌肉减少症，可能是由蛋白质合成减少、蛋白水解增加或由复杂的多因素机制控制的两个过程同时发生变化引起的。越来越多的证据表明氧化应激和活性氧 (ROS) 是蛋白水解的重要调节剂。我们之前的研究表明，CuZn 超氧化物歧化酶（CuZnSOD，Sod1) 在小鼠中导致氧化应激升高、肌肉萎缩和虚弱，以及与肌肉减少症相关的年龄相关表型加速。本研究的目的是确定氧化应激是否直接影响Sod1 ^-/-小鼠骨骼肌中蛋白水解的加速作为年龄的函数。与对照相比，Sod1 ^-/-肌肉显示蛋白质羰基和 3-硝基酪氨酸水平显着升高，表明存在高氧化和亚硝化蛋白质修饰。此外，Sod1中的年龄依赖性肌肉萎缩^-/-肌肉伴随着半胱氨酸蛋白酶、钙蛋白酶和 caspase-3 的上调，已知它们在萎缩条件下肌节的初始分解中起关键作用。此外，氧化应激诱导的肌肉萎缩的增加也与两种主要蛋白水解系统的同时激活密切相关，即泛素-蛋白酶体和溶酶体自噬途径。总之，我们的数据表明，Sod1 ^-/-小鼠中的慢性氧化应激通过增强蛋白水解系统的协调激活来加速年龄依赖性肌肉萎缩，从而导致整体蛋白质降解。