Overexpression of Galgt2 reduces dystrophic pathology in the skeletal muscles of alpha sarcoglycan-deficient mice.
Overexpression of Galgt2 reduces dystrophic pathology in the skeletal muscles of alpha sarcoglycan-deficient mice.
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DOI：
10.2353/ajpath.2009.080967
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发表时间：
2009-07
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影响因子：
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通讯作者：
Rui Xu;Sarah deVries;M. Camboni;Paul T. Martin
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文献类型：
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作者：
Rui Xu;Sarah deVries;M. Camboni;Paul T. Martin
最近的研究表明，在各种形式的肌营养不良症中，许多未突变的基因可以作为保护骨骼肌纤维免受损伤的替代物。其中一种基因是 Galgt2，在小鼠中也称为细胞毒性 T 细胞 GalNAc 转移酶。在这项研究中，我们发现 Galgt2 过度表达可减少缺乏 α 肌聚糖 (Sgca) 的小鼠骨骼肌中营养不良病理学的发展，Sgca 是一种 2D 肢带型肌营养不良症小鼠模型。 Galgt2 转基因 Sgca(-/-) 小鼠表现出肌纤维损伤水平降低，证据如下：i) 血清肌酸激酶活性水平正常，ii) 肌纤维缺乏伊文思蓝染料摄取，iii) 小鼠运动活性水平正常，以及 iv) 具有中心位置细胞核的肌纤维百分比接近正常。此外，通过组织病理学测量观察到，使用腺相关病毒基因治疗载体在出生后早期过度表达 Galgt2 可保护 Sgca(-/-) 肌纤维免受损伤。 Galgt2 转基因 Sgca(-/-) 小鼠的 α 肌聚糖与 CT 碳水化合物的糖基化水平也有所增加，但未显示 β、γ、δ 或 ε 肌聚糖的上调。这些数据与我们之前的研究结果相结合，表明 Galgt2 对三种不同形式的肌营养不良症具有治疗作用，因此可能具有治疗各种肌病的广泛治疗潜力。
Recent studies have shown that a number of genes that are not mutated in various forms of muscular dystrophy may serve as surrogates to protect skeletal myofibers from injury. One such gene is Galgt2, which is also called cytotoxic T cell GalNAc transferase in mice. In this study, we show that Galgt2 overexpression reduces the development of dystrophic pathology in the skeletal muscles of mice lacking alpha sarcoglycan (Sgca), a mouse model for limb girdle muscular dystrophy 2D. Galgt2 transgenic Sgca(-/-) mice showed reduced levels of myofiber damage, as evidenced by i) normal levels of serum creatine kinase activity, ii) a lack of Evans blue dye uptake into myofibers, iii) normal levels of mouse locomotor activity, and iv) near normal percentages of myofibers with centrally located nuclei. In addition, the overexpression of Galgt2 in the early postnatal period using an adeno-associated virus gene therapy vector protected Sgca(-/-) myofibers from damage, as observed using histopathology measurements. Galgt2 transgenic Sgca(-/-) mice also had increased levels of glycosylation of alpha dystroglycan with the CT carbohydrate, but showed no up-regulation of beta, gamma, delta, or epsilon sarcoglycan. These data, coupled with results from our previous studies, show that Galgt2 has therapeutic effects in three distinct forms of muscular dystrophy and may, therefore, have a broad spectrum of therapeutic potential for the treatment of various myopathies.