Mice lacking the superoxide anion scavenger CuZn superoxide dismutase (Sod1^−/− mice) develop a number of age-related phenotypes, including an early progression of muscle atrophy and weakness (sarcopenia) associated with loss of innervation. The purpose of this study was to delineate the early development of sarcopenia in the Sod1^−/− mice and to measure changes in the muscle transcriptome, proteome, and eicosanoid profile at the stage when sarcopenia is markedly induced in this model (7–9 months of age). We found a strong correlation between muscle atrophy and mitochondrial state 1 hydroperoxide production, which was 40% higher in isolated mitochondria from Sod1^−/− mouse gastrocnemius muscle by 2 months of age. The primary pathways showing altered gene expression in Sod1^−/− mice identified by RNA-seq transcriptomic analysis are protein ubiquitination, synaptic long-term potentiation, calcium signaling, phospholipase C signaling, AMPK, and TWEAK signaling. Targeted proteomics shows elevated expression of mitochondrial proteins, fatty acid metabolism enzymes, tricarboxylic acid (TCA) cycle enzymes, and antioxidants, while enzymes involved in carbohydrate metabolism are downregulated in Sod1^−/− mice. LC-MS analysis of lipids in gastrocnemius muscle detected 78 eicosanoids, of which 31 are significantly elevated in muscle from Sod1^−/− mice. These data suggest that mitochondrial hydroperoxide generation is elevated prior to muscle atrophy and may be a potential driving factor of changes in the transcriptome, proteome, and eicosanoid profile of the Sod1^−/− mice. Together, these analyses revealed important molecular events that occur during muscle atrophy, which will pave the way for future studies using new approaches to treat sarcopenia.

中文翻译：

---

肌肉减少症 CuZnSOD 缺失小鼠模型中肌肉萎缩的转录和代谢途径的分子变化。

缺乏超氧阴离子清除剂 CuZn 超氧化物歧化酶的小鼠（Sod1 ^-/-小鼠）会出现许多与年龄相关的表型，包括与神经支配丧失相关的肌肉萎缩和无力（少肌症）的早期进展。本研究的目的是描绘Sod1 ^-/-小鼠中肌肉减少症的早期发展，并在该模型中显着诱导肌肉减少症的阶段（7-9 个月）测量肌肉转录组、蛋白质组和类花生酸谱的变化。年龄）。我们发现肌肉萎缩与线粒体状态 1 氢过氧化物的产生之间存在很强的相关性，在从Sod1中分离出的线粒体中高出 40% ^-/-2个月大的小鼠腓肠肌。通过 RNA-seq 转录组分析鉴定的Sod1 ^-/-小鼠中显示基因表达改变的主要途径是蛋白质泛素化、突触长时程增强、钙信号传导、磷脂酶 C 信号传导、AMPK 和 TWEAK 信号传导。靶向蛋白质组学显示线粒体蛋白、脂肪酸代谢酶、三羧酸 (TCA) 循环酶和抗氧化剂的表达升高，而参与碳水化合物代谢的酶在Sod1 ^-/-小鼠中下调。腓肠肌中脂质的 LC-MS 分析检测到 78 种类花生酸，其中 31 种在Sod1的肌肉中显着升高^-/-老鼠。这些数据表明线粒体氢过氧化物的生成在肌肉萎缩之前升高，并且可能是Sod1 ^-/-小鼠的转录组、蛋白质组和类花生酸谱变化的潜在驱动因素。总之，这些分析揭示了肌肉萎缩期间发生的重要分子事件，这将为未来使用新方法治疗肌肉减少症的研究铺平道路。