Overexpression of osteoactivin protects skeletal muscle from severe degeneration caused by long-term denervation in mice.
Overexpression of osteoactivin protects skeletal muscle from severe degeneration caused by long-term denervation in mice.
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DOI：
10.2152/jmi.54.248
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发表时间：
2007-08-01
期刊：
影响因子：
--
通讯作者：
Nikawa, Takeshi
中科院分区：
文献类型：
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作者：
Furochi, Harumi;Tamura, Seiko;Nikawa, Takeshi
我们之前已经证明，骨活性素（一种在肌纤维中表达的 I 型膜糖蛋白）可以上调小鼠去神经骨骼肌成纤维细胞中基质金属蛋白酶 (MMP)-3 和 MMP-9 的表达。为了确定骨激活素介导的骨骼肌中 MMP 的增加是否有助于去神经骨骼肌的再生，我们对骨激活素转基因小鼠进行了 70 或 90 天的长期去神经支配。长期去神经支配导致野生型小鼠骨骼肌肌纤维严重变性和纤维化。然而，骨活性素的过度表达可以保护骨骼肌免受此类变化的影响。骨激活素转基因小鼠的骨骼肌长期去神经后，成纤维细胞样细胞的浸润和胶原沉积持续在低水平。去神经期间腓肠肌中再生/变性相关基因的表达支持了骨激活素的这种细胞保护作用。与野生型小鼠相比，去神经支配显着上调了骨激活素转基因小鼠腓肠肌中抗纤维化基因的表达，例如磷脂酰肌醇蛋白聚糖-1和核心蛋白聚糖-1。相反，骨活性素的过度表达导致去神经诱导的伸长因子1A-1表达显着减少，伸长因子1A-1是退化细胞持续存在的指标。我们的结果表明，骨激活素介导的骨骼肌中 MMP 的增加可能有助于保护受伤的肌肉免于纤维化，从而导致去神经后完全再生。
We have previously shown that osteoactivin, a type I membrane glycoprotein expressed in myofibers, upregulated expression of matrix metalloprotease (MMP)-3 and MMP-9 in fibroblasts infiltrated denervated skeletal muscle in mice. To address whether osteoactivin-mediated increase in MMPs in skeletal muscle is useful for regeneration of denervated skeletal muscle, we subjected osteoactivin-transgenic mice to long-term denervation for 70 or 90 days. Long-term denervation caused severe degeneration of myofibers and fibrosis in skeletal muscle of wild-type mice. However, overexpression of osteoactivin protected skeletal muscle from such changes. Infiltration of fibroblast-like cells and collagen deposition were sustained at low levels after long-term denervation in skeletal muscle of osteoactivin-transgenic mice. This cytoprotective effect of osteoactivin was supported by the expression of regeneration/degeneration-associated genes in the gastrocnemius muscle during denervation. Denervation significantly upregulated the expression of anti-fibrotic genes, such as glypican-1 and decorin-1, in the gastrocnemius muscle of osteoactivin-transgenic mice, compared with wild-type mice. In contrast, overexpression of osteoactivin caused a significant reduction in denervation-induced expression of elongation factor 1A-1, an indicator for the persistence of degenerated cells. Our results suggest that an osteoactivin-mediated increase in MMPs in skeletal muscle might be useful for protecting injured muscle from fibrosis, leading to full regeneration after denervation.