Abstract：
Duchenne muscular dystrophy (DMD) is an incurable disease caused by mutations in the X-linked DMD gene that encodes a structural muscle protein, dystrophin. This, in turn, leads to progressive degeneration of the skeletal muscles and the heart. Hydrogen sulfide (H2S), the pleiotropic agent with antioxidant, anti-inflammatory, and pro-angiogenic activities, could be considered a promising therapeutic factor for DMD. In this work, we studied the effect of daily intraperitoneal administration of the H2S donor, sodium hydrosulfide (NaHS, 100 μmol/kg/day for 5 weeks) on skeletal muscle (gastrocnemius, diaphragm and tibialis anterior) pathology in dystrophin-deficient mdx mice, characterized by decreased expression of H2S-generating enzymes. NaHS reduced the level of muscle damage markers in plasma (creatine kinase, lactate dehydrogenase and osteopontin). It lowered oxidative stress by affecting the GSH/GSSG ratio, up-regulating the level of cytoprotective heme oxygenase-1 (HO-1) and down-regulating the NF-κB pathway. In the gastrocnemius muscle, it also increased angiogenic vascular endothelial growth factor (Vegf) and its receptor (Kdr) expression, accompanied by the elevated number of α-SMA/CD31/lectin-positive blood vessels. The expression of fibrotic regulators, like Tgfβ, Col1a1 and Fn1 was decreased by NaHS in the tibialis anterior, while the level of autophagy markers (AMPKα signalling and Atg genes), was mostly affected in the gastrocnemius. Histological and molecular analysis showed no effect of H2S donor on regeneration and the muscle fiber type composition. Overall, the H2S donor modified the gene expression and protein level of molecules associated with the pathophysiology of DMD, contributing to the regulation of oxidative stress, inflammation, autophagy, and angiogenesis.
摘要：
杜氏肌营养不良症（DMD）是一种无法治愈的疾病，由编码结构肌肉蛋白的X连锁DMD基因突变引起，肌营养不良蛋白。这个,反过来,导致骨骼肌和心脏的进行性退化。硫化氢(H2S),具有抗氧化剂的多效性剂，抗炎,和促血管生成活性，可以被认为是DMD的有希望的治疗因素。在这项工作中,我们研究了每天腹膜内施用H2S供体的效果，硫氢化钠(NaHS，100μmol/kg/天，持续5周）对骨骼肌（腓肠肌，肌营养不良蛋白缺乏的mdx小鼠的diaphragm肌和胫骨前）病理学，以H2S生成酶的表达降低为特征。NaHS降低了血浆中肌肉损伤标志物的水平(肌酸激酶，乳酸脱氢酶和骨桥蛋白）。它通过影响GSH/GSSG比率来降低氧化应激，上调细胞保护性血红素加氧酶-1(HO-1)水平,下调NF-κB通路。在腓肠肌中，它还增加了血管生成血管内皮生长因子（Vegf）及其受体（Kdr）的表达，伴随着α-SMA/CD31/凝集素阳性血管数量的增加。纤维化调节因子的表达，像Tgfβ，胫骨前肌的Col1a1和Fn1被NaHS降低，而自噬标记（AMPKα信号和Atg基因）的水平，主要在腓肠肌受累。组织学和分子分析表明H2S供体对再生和肌纤维类型组成没有影响。总的来说,H2S供体改变了DMD病理生理学相关分子的基因表达和蛋白水平,有助于调节氧化应激，炎症,自噬,和血管生成。
