Abstract
Pseudotrophic muscular dystrophy is a common clinical skeletal muscle necrotic disease, among which Duchenne muscular dystrophy (DMD) is the predominant. For such diseases, there is no clinically effective treatment, which is only symptomatic or palliative treatment. Oxidative stress and chronic inflammation are common pathological features of DMD. In recent years, it has been found that the pathophysiological changes of skeletal muscle in DMD mice are related to muscle stem cell failure. In the present study, we established a DMD mice model and provided tocotrienol (γ-tocotrienol, GT3), an antioxidant compound, to explore the relationship between the physiological state of muscle stem cells and oxidative stress. The results showed that the application of GT3 can reduce ROS production and cellular proliferation in the muscle stem cells of DMD mice, which is beneficial to promote the recovery of muscle stem cell function in DMD mice. GT3 treatment improved the differentiation ability of muscle stem cells in DMD mice with increasing numbers of MyoD+ cells. GT3 application significantly decreased percentages of CD45+ cells and PDGFRα+ fibro-adipogenic progenitors in the tibialis anterior of DMD mice, indicating that the increased inflammation and fibro-adipogenic progenitors were attenuated in GT3-treated DMD mice. These data suggest that increased ROS production causes dysfunctional muscle stem cell in DMD mice, which might provide a new avenue to treat DMD patients in the clinic.
Highlights
Duchenne muscular dystrophy (DMD) is a recessive neuromuscular disease linked to the X chromosome
We separated the tibialis anterior muscle of wild type (WT) and DMD mice and weighed them for comparison, the weight of the tibialis anterior (TA) muscle of the left side showed that the muscle weight of DMD mice is significantly higher than that of WT mice (Figure 1B)
There is no significant difference in body weight between WT and DMD mice
Summary
DMD is a recessive neuromuscular disease linked to the X chromosome. The disease is mainly caused by frameshift deletion, meaningless or repeated mutations of the gene encoding dystrophin (dystrophin) on the X chromosome (Xp21.2) (Frank et al, 2020; Miyatake et al, 2016). Dystrophin is an important part of a protein complex, which connects the muscle cytoskeleton and extracellular matrix to maintain the integrity and Protection of γ-Tocotrienol on DMD stability of the muscle membrane (McGreevy et al, 2015). The extracellular C-terminal domain of dystrophin binds to β-dystrophic glycan, which acts as a bridge and anchor protein. The mutation of dystrophin leads to the disruption of dystrophin-related glycoprotein complexes, which causes membrane instability and sensitizes to various stresses and muscle fiber necrosis. DMD is a progressive disease (Ogura et al, 2014). The existing treatment approaches of DMD, such as steroid therapy, stem cell transplantation and gene therapy, have certain defects and limitations (Chamberlain and Chamberlain, 2017; Kole and Krieg, 2015; Lim et al, 2018)
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