Elevated levels of active matrix metalloproteinase-9 cause hypertrophy in skeletal muscle of normal and dystrophin-deficient mdx mice
Elevated levels of active matrix metalloproteinase-9 cause hypertrophy in skeletal muscle of normal and dystrophin-deficient mdx mice
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DOI：
10.1093/hmg/ddr362
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发表时间：
2011-11-15
影响因子：
3.5
通讯作者：
Kumar, Ashok
中科院分区：
文献类型：
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作者：
Dahiya, Saurabh;Bhatnagar, Shephali;Kumar, Ashok
基质金属蛋白酶（MMP）是一组细胞外蛋白酶，参与多种生理和病理生理条件下的组织重塑。虽然在多种情况下都在骨骼肌中观察到 MMP（尤其是 MMP-9）表达增加，但其生理意义仍不清楚。在本研究中，通过生成表达 MMP-9 组成型活性突变体（即 MMP-9G100L）的新型骨骼肌特异性转基因（Tg）小鼠，我们研究了 MMP-9 水平升高对体内骨骼肌结构和功能的影响。酶活性 MMP-9 蛋白的 Tg 表达显着增加骨骼肌纤维横截面积、收缩蛋白水平和等长收缩中的力产生。 MMP-9 刺激 Tg 小鼠中 Akt 信号通路的激活。此外，活性MMP-9的表达增加了小鼠比目鱼肌中快速型纤维的比例。 MMP-9 的过度表达还显着减少体内骨骼肌中 I 型和 IV 型胶原蛋白的沉积。在一岁的 mdx 小鼠（杜氏肌营养不良症 (DMD) 模型）中，Mmp9 基因的缺失可减少纤维肥大以及 Akt 和 p38 丝裂原激活蛋白激酶的磷酸化。总的来说，我们的研究表明，活性 MMP-9 蛋白水平升高会导致骨骼肌肥大，并且 MMP-9 水平的调节可能对包括 DMD 在内的各种肌肉疾病具有治疗价值。
Matrix metalloproteinases (MMPs) are a group of extracellular proteases involved in tissue remodeling in several physiological and pathophysiological conditions. While increased expression of MMPs (especially MMP-9) has been observed in skeletal muscle in numerous conditions, their physiological significance remains less-well understood. By generating novel skeletal muscle-specific transgenic (Tg) mice expressing constitutively active mutant of MMP-9 (i.e. MMP-9G100L), in this study, we have investigated the effects of elevated levels of MMP-9 on skeletal muscle structure and function in vivo. Tg expression of enzymatically active MMP-9 protein significantly increased skeletal muscle fiber cross-section area, levels of contractile proteins and force production in isometric contractions. MMP-9 stimulated the activation of the Akt signaling pathway in Tg mice. Moreover, expression of active MMP-9 increased the proportion of fast-type fiber in soleus muscle of mice. Overexpression of MMP-9 also considerably reduced the deposition of collagens I and IV in skeletal muscle in vivo. In one-year-old mdx mice (a model for Duchenne muscular dystrophy, DMD), deletion of the Mmp9 gene reduced fiber hypertrophy and phosphorylation of Akt and p38 mitogen-activated protein kinase. Collectively, our study suggests that elevated levels of active MMP-9 protein cause hypertrophy in skeletal muscle and that the modulation of MMP-9 levels may have therapeutic value in various muscular disorders including DMD.