Cardiac and Skeletal Muscle Defects in a Mouse Model of Human Barth Syndrome
Cardiac and Skeletal Muscle Defects in a Mouse Model of Human Barth Syndrome
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DOI：
10.1074/jbc.m110.171439
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发表时间：
2011-01-14
影响因子：
4.8
通讯作者：
Khuchua, Zaza
中科院分区：
文献类型：
--
作者：
Acehan, Devrim;Vaz, Frederic;Khuchua, Zaza
Barth综合征是由Tafazzin（TAZ）基因突变引起的一种X连锁遗传疾病，其特征是心肌病，运动不耐受，慢性疲劳，延迟生长和中性粒细胞减少。 Tafazzin是心脏磷脂重塑所需的线粒体透射酶。尽管在非哺乳动物模型生物中已经研究了塔法蛋白功能，但尚未使用哺乳动物遗传遗传丧失方法。我们检查了塔法津敲低对小鼠肌膜线粒体和心脏功能的后果。 Tafazzin敲低导致心脏和骨骼肌中四边形心脏脂蛋白的急剧下降，并积累单层肌蛋白脂肪素和心脏磷脂分子种类异常。电子显微镜揭示了线粒体，肌原纤维和骨骼肌和心脏肌肉中与线粒体相关的膜的病理变化。超声心动图和磁共振成像显示出严重的心脏异常，包括左心室扩张，左心室质量减少以及tafazzin缺陷小鼠的分数缩短和射血分数的抑郁。 Tafazzin敲低小鼠提供了第一个用于Barth综合征的哺乳动物模型系统，其中线粒体磷脂含量改变，超微结构异常，心肌和线粒体功能障碍以及临床结果之间的病理生理关系。
Barth syndrome is an X-linked genetic disorder caused by mutations in the tafazzin (taz) gene and characterized by dilated cardiomyopathy, exercise intolerance, chronic fatigue, delayed growth, and neutropenia. Tafazzin is a mitochondrial transacylase required for cardiolipin remodeling. Although tafazzin function has been studied in non-mammalian model organisms, mammalian genetic loss of function approaches have not been used. We examined the consequences of tafazzin knockdown on sarcomeric mitochondria and cardiac function in mice. Tafazzin knockdown resulted in a dramatic decrease of tetralinoleoyl cardiolipin in cardiac and skeletal muscles and accumulation of monolysocardiolipins and cardiolipin molecular species with aberrant acyl groups. Electron microscopy revealed pathological changes in mitochondria, myofibrils, and mitochondrion-associated membranes in skeletal and cardiac muscles. Echocardiography and magnetic resonance imaging revealed severe cardiac abnormalities, including left ventricular dilation, left ventricular mass reduction, and depression of fractional shortening and ejection fraction in tafazzin-deficient mice. Tafazzin knockdown mice provide the first mammalian model system for Barth syndrome in which the pathophysiological relationships between altered content of mitochondrial phospholipids, ultrastructural abnormalities, myocardial and mitochondrial dysfunction, and clinical outcome can be completely investigated.