Metabolic conditions such as obesity, insulin resistance and glucose intolerance are frequently associated with impairments in skeletal muscle function and metabolism. This is often linked to dysregulation of homeostatic pathways including an increase in reactive oxygen species (ROS) and oxidative stress. One of the main sites of ROS production is the mitochondria, where the flux of substrates through the electron transport chain (ETC) can result in the generation of oxygen free radicals. Fortunately, several mechanisms exist to buffer bursts of intracellular ROS and peroxide production, including the enzymes Catalase, Glutathione Peroxidase and Superoxide Dismutase (SOD). Of the latter, there are two intracellular isoforms; SOD1 which is mostly cytoplasmic, and SOD2 which is found exclusively in the mitochondria. Developmental and chronic loss of these enzymes has been linked to disease in several studies, however the temporal effects of these disturbances remain largely unexplored. Here, we induced a post-developmental (8-week old mice) deletion of SOD2 in skeletal muscle (SOD2-iMKO) and demonstrate that 16 weeks of SOD2 deletion leads to no major impairment in whole body metabolism, despite these mice displaying alterations in aspects of mitochondrial abundance and voluntary ambulatory movement. This is likely partly explained by the suggestive data that a compensatory response may exist from other redox enzymes, including catalase and glutathione peroxidases. Nevertheless, we demonstrated that inducible SOD2 deletion impacts on specific aspects of muscle lipid metabolism, including the abundance of phospholipids and phosphatidic acid (PA), the latter being a key intermediate in several cellular signaling pathways. Thus, our findings suggest that post-developmental deletion of SOD2 induces a more subtle phenotype than previous embryonic models have shown, allowing us to highlight a previously unrecognized link between SOD2, mitochondrial function and bioactive lipid species including PA.

诸如肥胖、胰岛素抵抗和葡萄糖耐受不良等代谢状况通常与骨骼肌功能和代谢受损有关。这通常与体内平衡通路的失调有关，包括活性氧 (ROS) 和氧化应激的增加。ROS 产生的主要场所之一是线粒体，其中底物通过电子传递链 (ETC) 的流动可导致氧自由基的产生。幸运的是，存在几种机制来缓冲细胞内 ROS 和过氧化物产生的爆发，包括酶过氧化氢酶、谷胱甘肽过氧化物酶和超氧化物歧化酶 (SOD)。在后者中，有两种细胞内亚型；SOD1 主要存在于细胞质中，而 SOD2 仅存在于线粒体中。在几项研究中，这些酶的发育和慢性丧失与疾病有关，但这些干扰的时间影响在很大程度上仍未得到探索。在这里，我们诱导骨骼肌中 SOD2 的发育后（8 周龄小鼠）缺失 (SOD2-iMKO)，并证明 16 周的 SOD2 缺失不会导致全身代谢发生重大损害，尽管这些小鼠表现出改变线粒体丰度和自愿走动运动的各个方面。这可能部分解释为暗示性数据可能存在来自其他氧化还原酶的补偿反应，包括过氧化氢酶和谷胱甘肽过氧化物酶。尽管如此，我们证明了可诱导的 SOD2 缺失对肌肉脂质代谢的特定方面有影响，包括磷脂和磷脂酸 (PA) 的丰度，后者是几种细胞信号通路中的关键中间体。因此，我们的研究结果表明，SOD2 的发育后缺失诱导的表型比以前的胚胎模型显示的更微妙，这使我们能够强调 SOD2、线粒体功能和包括 PA 在内的生物活性脂质种类之间以前未被认识的联系。