Myofiber-specific inhibition of TGFβ signaling protects skeletal muscle from injury and dystrophic disease in mice
Myofiber-specific inhibition of TGFβ signaling protects skeletal muscle from injury and dystrophic disease in mice
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DOI：
10.1093/hmg/ddu413
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发表时间：
2014-12-20
影响因子：
3.5
通讯作者：
Molkentin, Jeffery D.
中科院分区：
文献类型：
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作者：
Accornero, Federica;Kanisicak, Onur;Molkentin, Jeffery D.
肌营养不良症(MD)是一种以骨骼肌坏死和纤维组织进行性积聚为特征的疾病。虽然转化生长因子-β已成为MD和纤维化疾病的中心效应因子，但作为TGFO依赖病理基础的病变肌肉中的细胞类型尚未分离。在这里，我们产生了肌纤维特异性抑制转化生长因子β信号的转基因小鼠，这是由于表达转化生长因子βII型受体显性阴性(dn转化生长因子βRII)截断突变体。DnTGFβRII在肌纤维中的表达通过降低肌纤维膜脆性的机制减轻了Delta-肌聚糖缺失(SGCD(-/-))小鼠的营养不良表型。DnTGFβRII转基因还减轻了肌肉损伤，改善了心脏毒素损伤后的肌肉再生，并增加了卫星细胞的数量和活性。一项无偏见的全球表达分析揭示了dnTGFβRII介导的保护作用的一些潜在机制，其中之一是诱导抗氧化蛋白金属硫蛋白(MT)。事实上，转化生长因子β在体外直接抑制mt基因的表达，dnTGFβRII转基因对营养不良肌肉中的活性氧积累具有保护作用，体内类似mt的治疗可以保护骨骼肌损伤时的骨骼肌，并改善营养不良肌纤维的膜稳定性。因此，我们的结果表明，肌纤维是MD中与转化生长因子β信号相关的有害影响的中心媒介。
Muscular dystrophy (MD) is a disease characterized by skeletal muscle necrosis and the progressive accumulation of fibrotic tissue. While transforming growth factor (TGF)-beta has emerged as central effector of MD and fibrotic disease, the cell types in diseased muscle that underlie TGFO-dependent pathology have not been segregated. Here, we generated transgenic mice with myofiber-specific inhibition of TGF beta signaling owing to expression of a TGF beta type II receptor dominant-negative (dnTGF beta RII) truncation mutant. Expression of dnTGF beta RII in myofibers mitigated the dystrophic phenotype observed in delta-sarcoglycan-null (Sgcd(-/-)) mice through a mechanism involving reduced myofiber membrane fragility. The dnTGF beta RII transgene also reduced muscle injury and improved muscle regeneration after cardiotoxin injury, as well as increased satellite cell numbers and activity. An unbiased global expression analysis revealed a number of potential mechanisms for dnTGF beta RII-mediated protection, one of which was induction of the antioxidant protein metallothionein (Mt). Indeed, TGF beta directly inhibited Mt gene expression in vitro, the dnTGF beta RII transgene conferred protection against reactive oxygen species accumulation in dystrophic muscle and treatment with Mt mimetics protected skeletal muscle upon injury in vivo and improved the membrane stability of dystrophic myofibers. Hence, our results show that the myofibers are central mediators of the deleterious effects associated with TGF beta signaling in MD.