Abstract
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.
Highlights
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophies [1], which affects one in 5000-6000 male births [2]
Lack of transcriptionally active nuclear factor erythroid 2-related factor 2 (Nrf2) enhances skeletal muscle damage after CTX-induced injury To analyze the effect of Nrf2 transcriptional deficiency during acute muscle damage, we examined inflammatory reaction and muscle degeneration as well as regeneration in the model of CTX-induced myoinjury
Muscle regeneration is not affected in the absence of transcriptionally active Nrf2 following CTX-induced injury To assess the role of Nrf2 during muscle regeneration following the acute muscle injury caused by CTX injection, we examined the mRNA level of Myosin heavy chain 3 (Myh3) and the number of embryonic myosin heavy chain (eMyHC)+ myofibers
Summary
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophies [1], which affects one in 5000-6000 male births [2]. DMD is the lethal Xchromosome linked recessive genetic neuromuscular disorder, caused by mutations in the gene encoding dystrophin [1]. Dystrophin deficiency leads to progressive muscle weakness, severe muscular atrophy, cardiomyopathy, and respiratory impairments, the two latter being the leading causes of mortality among patients with DMD [2]. The loss of dystrophin disrupts the complex resulting in sarcolemmal instability that makes cells more susceptible to damage and leads to necrosis of muscle fibers [3]. It results in the activation of the innate immune system, excessive inflammatory response, and increased oxidative stress [4]
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