The nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as a master cytoprotective factor regulating the expression of genes encoding anti-oxidant, anti-inflammatory, and detoxifying proteins. The role of Nrf2 in the pathophysiology of skeletal muscles has been evaluated in different experimental models, however, due to inconsistent data, we aimed to investigate how Nrf2 transcriptional deficiency (Nrf2tKO) affects muscle functions both in an acute and chronic injury. The acute muscle damage was induced in mice of two genotypes—WT and Nrf2tKO mice by cardiotoxin (CTX) injection. To investigate the role of Nrf2 in chronic muscle pathology, mdx mice that share genetic, biochemical, and histopathological features with Duchenne muscular dystrophy (DMD) were crossed with mice lacking transcriptionally active Nrf2 and double knockouts (mdx/Nrf2tKO) were generated. To worsen the dystrophic phenotype, the analysis of disease pathology was also performed in aggravated conditions, by applying a long-term treadmill test. We have observed slightly increased muscle damage in Nrf2tKO mice after CTX injection. Nevertheless, transcriptional ablation of Nrf2 in mdx mice did not significantly aggravate the most deleterious, pathological hallmarks of DMD related to degeneration, inflammation, fibrotic scar formation, angiogenesis, and the number and proliferation of satellite cells in non-exercised conditions. On the other hand, upon chronic exercises, the degeneration and inflammatory infiltration of the gastrocnemius muscle, but not the diaphragm, turned to be increased in Nrf2tKOmdx in comparison to mdx mice. In conclusion, the lack of transcriptionally active Nrf2 influences moderately muscle pathology in acute CTX-induced muscle injury and chronic DMD mouse model, without affecting muscle functionality. Hence, in general, we demonstrated that the deficiency of Nrf2 transcriptional activity has no profound impact on muscle pathology in various models of muscle injury.

中文翻译：

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Nrf2在急慢性肌肉损伤中的作用

核因子红细胞 2 相关因子 2 (Nrf2) 被认为是一种主要的细胞保护因子，可调节编码抗氧化、抗炎和解毒蛋白的基因的表达。Nrf2 在骨骼肌病理生理学中的作用已在不同的实验模型中进行了评估，然而，由于数据不一致，我们旨在研究 Nrf2 转录缺陷 (Nrf2tKO) 如何影响急性和慢性损伤中的肌肉功能。通过注射心脏毒素（CTX）在两种基因型小鼠 - WT 和 Nrf2tKO 小鼠中诱导急性肌肉损伤。为了研究 Nrf2 在慢性肌肉病理学中的作用，mdx 小鼠共享遗传、生化、将杜氏肌营养不良症 (DMD) 和组织病理学特征与缺乏转录活性 Nrf2 的小鼠杂交，并产生双敲除 (mdx/Nrf2tKO)。为了使营养不良表型恶化，还在加重的情况下通过应用长期跑步机测试对疾病病理进行分析。我们观察到 CTX 注射后 Nrf2tKO 小鼠的肌肉损伤略有增加。尽管如此，mdx 小鼠中 Nrf2 的转录消融并未显着加重 DMD 最有害的病理特征，这些特征与退化、炎症、纤维化瘢痕形成、血管生成以及非运动条件下卫星细胞的数量和增殖有关。另一方面，在长期运动中，腓肠肌的退化和炎症浸润，但不是隔膜，与 mdx 小鼠相比，Nrf2tKOmdx 中的隔膜增加了。总之，在急性 CTX 诱导的肌肉损伤和慢性 DMD 小鼠模型中，转录活性 Nrf2 的缺乏会适度影响肌肉病理，而不影响肌肉功能。因此，总的来说，我们证明了 Nrf2 转录活性的缺乏对各种肌肉损伤模型中的肌肉病理学没有深远的影响。