Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice.

IF 5.3 2区医学 Q2 CELL BIOLOGY

Skeletal Muscle Pub Date : 2024-06-12 DOI:10.1186/s13395-024-00346-2

Urszula Florczyk-Soluch, Katarzyna Polak, Sarka Jelinkova, Iwona Bronisz-Budzyńska, Reece Sabo, Subhashini Bolisetty, Anupam Agarwal, Ewa Werner, Alicja Józkowicz, Jacek Stępniewski, Krzysztof Szade, Józef Dulak

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引用次数: 0

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;HMOX1^Pax7Ind) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1^Pax7Ind 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;HMOX1^Pax7Ind 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^Pax7Ind 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.

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在卫星细胞中靶向表达血红素加氧酶-1可改善营养不良小鼠的骨骼肌病理变化。

背景：成肌驻留的肌源性干细胞--卫星细胞（SCs）在肌肉再生中发挥着不可替代的作用，但在杜氏肌营养不良症（DMD）中却受到了内在损害。此前我们发现，肌营养不良性卫星细胞表达低水平的抗炎和抗氧化血红素加氧酶-1（HO-1，HMOX1）。在此，我们评估了靶向诱导 HMOX1 是否会影响 SC 功能并减轻 DMD 的标志性症状：我们建立了双转基因小鼠模型（mdx;HMOX1Pax7Ind），该模型允许他莫昔芬（TX）诱导 HMOX1 在萎缩性肌肉的 Pax7 阳性细胞中表达。对Mdx;HMOX1Pax7Ind和对照组mdx小鼠进行为期5天的TX注射（75毫克/千克体重），然后进行高速跑步机（12米/分钟，45分钟）和下坡跑的急性运动方案，以恶化骨骼肌表型并揭示HO-1对肌肉病理和SC功能的直接影响：结果：HMOX1诱导导致mdx;HMOX1Pax7Ind小鼠（与mdx小鼠相比）的SC池下降，而体育锻炼的效果并不显著。体育锻炼时，mdx小鼠的SC和活化的CD34- SC亚群的增殖受到了影响，但这种影响在mdx;HMOX1Pax7Ind小鼠中得到了逆转，在车辆和TX处理的动物中都是如此。这与骨骼肌中HO-1的表达模式一致。在组织水平上，HO-1转基因动物的mdx小鼠选择性骨骼肌坏死事件和相关的肌肉损伤标志物循环水平的增加在HO-1转基因动物中被减弱，HO-1转基因动物还表现出抗炎性细胞因子特征（与mdx相比）：结论：HMOX1 的靶向表达对 DMD 起着保护作用，可减轻萎缩性肌肉病理变化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.