Florczyk-Soluch Urszula, Polak Katarzyna, Jelinkova Sarka, Bronisz-Budzyńska Iwona, Sabo Reece, Bolisetty Subhashini, Agarwal Anupam, Werner Ewa, Józkowicz Alicja, Stępniewski Jacek, Szade Krzysztof, Dulak Józef
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Kraków, Poland.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Skelet Muscle. 2024 Jun 12;14(1):13. doi: 10.1186/s13395-024-00346-2.
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.
We generated double-transgenic mouse model (mdx;HMOX1) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1 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.
HMOX1 induction caused a drop in SC pool in mdx;HMOX1 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;HMOX1 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).
Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.
成体肌肉驻留性肌源性干细胞，即卫星细胞（SCs），在肌肉再生中发挥着不可替代的作用，在杜兴氏肌营养不良症（DMD）中其内在功能受损。此前我们发现，营养不良的卫星细胞中抗炎和抗氧化的血红素加氧酶-1（HO-1，HMOX1）表达水平较低。在此，我们评估靶向诱导HMOX1是否会影响卫星细胞功能并减轻DMD的标志性症状。
我们构建了双转基因小鼠模型（mdx;HMOX1），该模型可使他莫昔芬（TX）诱导营养不良肌肉中Pax7阳性细胞表达HMOX1。对mdx;HMOX1和对照mdx小鼠进行为期5天的TX注射（75 mg/kg体重），随后采用高速跑步机（12 m/分钟，45分钟）进行急性运动方案和下坡跑，以加重骨骼肌表型并揭示HO-1对肌肉病理学和卫星细胞功能的即时影响。
HMOX1诱导导致mdx;HMOX1小鼠（与mdx对照小鼠相比）的卫星细胞池减少，同时并未加剧体育锻炼的影响。体育锻炼后，mdx小鼠中卫星细胞和活化的CD34卫星细胞亚群的增殖受损，而在mdx;HMOX1小鼠中这种影响得到逆转，无论是在接受载体处理还是TX处理的动物中均如此。这与骨骼肌中HO-1的表达模式相对应。在组织水平上，HO-1转基因动物中mdx小鼠选择性骨骼肌的坏死事件以及肌肉损伤标志物循环水平的相关增加均得到缓解，这些动物还表现出抗炎细胞因子谱（与mdx相比）。
HMOX1的靶向表达在DMD中发挥保护作用，并减轻营养不良性肌肉病变。
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