Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency
Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency
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DOI：
10.1038/ng1270
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发表时间：
2003-12-01
期刊：
影响因子：
30.8
通讯作者：
Bonaldo, P
中科院分区：
文献类型：
--
作者：
Irwin, WA;Bergamin, N;Bonaldo, P
VI 胶原蛋白是一种细胞外基质蛋白，可在骨骼肌和其他器官中形成微丝网络(1-3)。人类编码胶原蛋白 VI 的基因的遗传性突变会导致两种肌肉疾病：贝特莱姆肌病和乌尔里希先天性肌营养不良症 (4,5)。我们之前培育了 VI 型胶原蛋白缺陷 (Col6a1(-/-)) 小鼠，并表明它们的肌肉表型与 Bethlem 肌病非常相似(6)。导致肌病的病理生理学缺陷和机制尚不清楚。在这里，我们发现 Col6a1(-/-) 肌肉收缩强度的丧失与肌浆网 (SR) 和线粒体的超微结构改变以及自发细胞凋亡有关。我们在与选择性 F1FO-ATPase 抑制剂寡霉素一起孵育的 Col6a1(-/-) 小鼠的肌纤维中发现潜在的线粒体功能障碍，导致线粒体去极化、Ca2+ 失调和细胞凋亡增加。这些缺陷是可逆的，因为可以通过将 Col6a1(-/-) 肌纤维铺在 VI 型胶原上或添加环孢菌素 A (CsA)（线粒体通透性转换孔 (PTP) 抑制剂）来使其正常化。用CsA治疗Col6a1(-/-)小鼠可以挽救肌肉超微结构缺陷并显着减少体内凋亡细胞核的数量。这些发现表明，VI 型胶原肌病具有意想不到的线粒体发病机制，可用于治疗干预。
Collagen VI is an extracellular matrix protein that forms a microfilamentous network in skeletal muscles and other organs(1-3). Inherited mutations in genes encoding collagen VI in humans cause two muscle diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy(4,5). We previously generated collagen VI deficient (Col6a1(-/-)) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy(6). The pathophysiological defects and mechanisms leading to the myopathic disorder were not known. Here we show that Col6a1(-/-) muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. We found a latent mitochondrial dysfunction in myofibers of Col6a1(-/-) mice on incubation with the selective F1FO-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ deregulation and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1(-/-) myofibers on collagen VI or by addition of cyclosporin A (CsA), the inhibitor of mitochondrial permeability transition pore (PTP). Treatment of Col6a1(-/-) mice with CsA rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicate that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention.