PDF(Pubmed)
Abstract：
BACKGROUND: Adult muscle-resident myogenic stem cells, satellite cells (SCs), that play non-redundant role in muscle regeneration, are intrinsically impaired in Duchenne muscular dystrophy (DMD). Previously we revealed that dystrophic SCs express low level of anti-inflammatory and anti-oxidative heme oxygenase-1 (HO-1, HMOX1). Here we assess whether targeted induction of HMOX1 affect SC function and alleviates hallmark symptoms of DMD.
METHODS: We generated double-transgenic mouse model (mdx;HMOX1Pax7Ind) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1Pax7Ind and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function.
RESULTS: HMOX1 induction caused a drop in SC pool in mdx;HMOX1Pax7Ind mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34- SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1Pax7Ind mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx).
CONCLUSIONS: Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.
METHODS: We generated double-transgenic mouse model (mdx;HMOX1Pax7Ind) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1Pax7Ind and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function.
RESULTS: HMOX1 induction caused a drop in SC pool in mdx;HMOX1Pax7Ind mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34- SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1Pax7Ind mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx).
CONCLUSIONS: Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.
摘要：
背景：成年肌源性干细胞，卫星细胞（SC），在肌肉再生中发挥非冗余作用，在杜氏肌营养不良症（DMD）中固有地受损。以前我们揭示了营养不良的SCs表达低水平的抗炎和抗氧化血红素加氧酶-1（HO-1，HMOX1）。在这里，我们评估HMOX1的靶向诱导是否会影响SC功能并减轻DMD的标志性症状。
方法：我们产生了双转基因小鼠模型（mdx;HMOX1Pax7Ind），该模型允许他莫昔芬（TX）诱导的HMOX1在营养不良肌肉的Pax7阳性细胞中表达。Mdx;HMOX1Pax7Ind和对照mdx小鼠进行5天TX注射（75mg/kgb.w.），然后进行高速跑步机的急性运动方案（12m/min，45分钟）和下坡跑步使骨骼肌表型恶化，并揭示HO-1对肌肉病理和SC功能的直接影响。
结果：HMOX1诱导导致mdx中SC池下降；HMOX1Pax7Ind小鼠（与MDX同行)，同时不夸大体育锻炼的效果。在体育锻炼中，SCs和活化的CD34-SC亚群的增殖，在MDX小鼠中受损，在mdx中逆转的效应；HMOX1Pax7Ind小鼠，然而,在车辆和TX处理的动物中。这对应于骨骼肌中HO-1表达的模式。在组织层面,在HO-1转基因动物中，mdx小鼠选择性骨骼肌的坏死事件和相关的肌肉损伤标志物循环水平的增加被钝化，这也显示出抗炎细胞因子谱（与mdx）。
结论：HMOX1的靶向表达在DMD中起保护作用，减轻营养不良性肌肉病理。
方法：我们产生了双转基因小鼠模型（mdx;HMOX1Pax7Ind），该模型允许他莫昔芬（TX）诱导的HMOX1在营养不良肌肉的Pax7阳性细胞中表达。Mdx;HMOX1Pax7Ind和对照mdx小鼠进行5天TX注射（75mg/kgb.w.），然后进行高速跑步机的急性运动方案（12m/min，45分钟）和下坡跑步使骨骼肌表型恶化，并揭示HO-1对肌肉病理和SC功能的直接影响。
结果：HMOX1诱导导致mdx中SC池下降；HMOX1Pax7Ind小鼠（与MDX同行)，同时不夸大体育锻炼的效果。在体育锻炼中，SCs和活化的CD34-SC亚群的增殖，在MDX小鼠中受损，在mdx中逆转的效应；HMOX1Pax7Ind小鼠，然而,在车辆和TX处理的动物中。这对应于骨骼肌中HO-1表达的模式。在组织层面,在HO-1转基因动物中，mdx小鼠选择性骨骼肌的坏死事件和相关的肌肉损伤标志物循环水平的增加被钝化，这也显示出抗炎细胞因子谱（与mdx）。
结论：HMOX1的靶向表达在DMD中起保护作用，减轻营养不良性肌肉病理。
