Enhanced Na+/H+ exchange activity contributes to the pathogenesis of muscular dystrophy via involvement of p2 receptors
Enhanced Na+/H+ exchange activity contributes to the pathogenesis of muscular dystrophy via involvement of p2 receptors
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DOI：
10.2353/ajpath.2007.070452
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发表时间：
2007-11-01
影响因子：
6
通讯作者：
Wakabayashi, Shigeo
中科院分区：
文献类型：
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作者：
Iwata, Yuko;Katanosaka, Yuki;Wakabayashi, Shigeo
肌营养不良症的一个子集是由肌营养不良蛋白相关糖蛋白复合物的遗传缺陷引起的。使用两种动物模型（BIO14.6仓鼠和mdx小鼠），我们发现Na+/H+交换器（NHE）抑制剂防止肌肉变性。在1310个肌管中，NHE活性组成性增强，如通过升高的细胞内pH和增强的Na-22（+）内流以及假定的上游激酶ERK 42/44的激活所证明的。NHE抑制剂显著降低了基线细胞内Ca ~（2+）和Na ~+浓度的增加以及牵张诱导的损伤，表明Na ~+依赖性Ca ~（2+）超载通过Na ~+/Ca ~（2+）交换可能导致肌肉损伤。此外，发现ATP以通过拉伸进一步刺激的方式从BIO肌管连续释放，并且P2受体拮抗剂降低增强的NHE活性和营养不良性肌肉损伤。这些观察结果表明，自分泌ATP的释放可能主要参与营养不良的肌肉中的异常离子稳态的成因和Na+依赖性离子交换剂在肌营养不良症中发挥关键的病理作用。
A subset of muscular dystrophy is caused by genetic defects in dystrophin-associated glycoprotein complex. Using two animal models (BIO14.6 hamsters and mdx mice), we found that Na+/H+ exchanger (NHE) inhibitors prevented muscle degeneration. NHE activity was constitutively enhanced in 1310 myotubes, as evidenced by die elevated intracellular pH and enhanced Na-22(+) influx, with activation of putative upstream kinases ERK42/44. NHE inhibitor significantly reduced the increases in baseline intracellular Ca2+ as well as Na+ concentration and stretch-induced damage, suggesting that Na+ (i)-dependent Ca(2+)overload via the Na+/Ca2+ exchanger may cause muscle damage. Furthermore, ATP was found to be released continuously from BIO myotubes in a manner further stimulated by stretching and that the P2 receptor antagonists reduce the enhanced NHE activity and dystrophic muscle damage. These observations suggest that autocrine ATP release may be primarily involved in genesis of abnormal ionic homeostasis in dystrophic muscles and that Na+-dependent ion exchangers play a critical pathological role in muscular dystrophy.