Enhancing Muscle Membrane Repair by Gene Delivery of MG53 Ameliorates Muscular Dystrophy and Heart Failure in δ-Sarcoglycan-deficient Hamsters
Enhancing Muscle Membrane Repair by Gene Delivery of MG53 Ameliorates Muscular Dystrophy and Heart Failure in δ-Sarcoglycan-deficient Hamsters
复制标题
DOI：
10.1038/mt.2012.5
复制
发表时间：
2012-04-01
影响因子：
12.4
通讯作者：
Xiao, Xiao
中科院分区：
文献类型：
--
作者：
He, Bo;Tang, Ru-hang;Xiao, Xiao
肌营养不良 (MD) 是由 30 多个不同基因的基因突变引起的，其中许多基因编码对肌肉细胞结构和膜的完整性至关重要的蛋白质。它们的缺陷导致肌肉容易受到机械和生化损伤，导致膜渗漏、营养不良病理，并最终导致肌肉细胞损失。最近的研究报告称 MG53 是一种肌肉特异性 TRIM 家族蛋白，在肌膜修复中发挥着重要作用。在这里，我们表明，通过重组腺相关病毒（AAV）载体全身递送和肌肉特异性过度表达人MG53基因，可以增强δ-肌聚糖（δ-SG）缺陷的TO-2仓鼠（MD和充血性心力衰竭的动物模型）的膜修复，改善病理学，并改善肌肉和心脏功能。此外，MG53过表达增加了dysferlin水平，并通过caveolin-3的参与促进其转运至肌肉膜。 MG53 还通过激活细胞存活激酶（例如 Akt、细胞外信号调节激酶 (ERK1/2) 和糖原合成酶激酶 3 beta (GSK-3 beta)）以及抑制促凋亡蛋白 Bax 来保护肌肉细胞。我们的结果表明，增强肌肉膜修复机制可能是治疗 MD 和心肌病的一种新方法，正如肢带 MD (LGMD) 2F 模型所证明的那样。
Muscular dystrophies (MDs) are caused by genetic mutations in over 30 different genes, many of which encode for proteins essential for the integrity of muscle cell structure and membrane. Their deficiencies cause the muscle vulnerable to mechanical and biochemical damages, leading to membrane leakage, dystrophic pathology, and eventual loss of muscle cells. Recent studies report that MG53, a muscle-specific TRIM-family protein, plays an essential role in sarcolemmal membrane repair. Here, we show that systemic delivery and muscle-specific overexpression of human MG53 gene by recombinant adeno-associated virus (AAV) vectors enhanced membrane repair, ameliorated pathology, and improved muscle and heart functions in delta-sarcoglycan (delta-SG)-deficient TO-2 hamsters, an animal model of MD and congestive heart failure. In addition, MG53 overexpression increased dysferlin level and facilitated its trafficking to muscle membrane through participation of caveolin-3. MG53 also protected muscle cells by activating cell survival kinases, such as Akt, extracellular signal-regulated kinases (ERK1/2), and glycogen synthase kinase-3 beta (GSK-3 beta) and inhibiting proapoptotic protein Bax. Our results suggest that enhancing the muscle membrane repair machinery could be a novel therapeutic approach for MD and cardiomyopathy, as demonstrated here in the limb girdle MD (LGMD) 2F model.