MUSCLE-SPECIFIC OVEREXPRESSION OF LIPOPROTEIN-LIPASE CAUSES A SEVERE MYOPATHY CHARACTERIZED BY PROLIFERATION OF MITOCHONDRIA AND PEROXISOMES IN TRANSGENIC MICE
MUSCLE-SPECIFIC OVEREXPRESSION OF LIPOPROTEIN-LIPASE CAUSES A SEVERE MYOPATHY CHARACTERIZED BY PROLIFERATION OF MITOCHONDRIA AND PEROXISOMES IN TRANSGENIC MICE
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DOI：
10.1172/jci118145
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发表时间：
1995-08-01
影响因子：
15.9
通讯作者：
ZECHNER, R
中科院分区：
文献类型：
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作者：
LEVAKFRANK, S;RADNER, H;ZECHNER, R
在肝外组织中，脂蛋白脂肪酶 (LPL) 水解甘油三酯，从而产生用于组织摄取和代谢的 FFA。为了研究肌肉组织中 FFA 摄取增加的影响，使用由肌肉肌酸激酶基因启动子驱动的人 LPL 小基因产生了转基因小鼠系。在这些小鼠中，人 LPL 在骨骼肌和心肌中表达，但不在其他组织中表达。与 LPL 过表达水平成比例，血浆减少在三个独立的转基因小鼠品系中观察到甘油三酯水平、肌肉组织摄取FFA升高、体重减轻和过早死亡。这些动物出现了严重的肌病，其特征是肌纤维变性、纤维萎缩、糖原储存以及线粒体和过氧化物酶的广泛增殖。这种增殖程度表明FFA在这些细胞器的生物发生中发挥着重要作用。我们的实验表明，LPL是甘油三酯衍生的FFA对肌肉组织供应的速率限制。肌肉 LPL 调节不当可导致重大病理变化，并且可能在某些人类肌病的发病机制中发挥重要作用。肌肉特异性 LPL 转基因小鼠系将作为研究肌病以及线粒体和过氧化物酶体生物发生的有用动物模型。
In extrahepatic tissues lipoprotein lipase (LPL) hydrolyzes triglycerides thereby generating FFA for tissue uptake and metabolism, To study the effects of increased FFA uptake in muscle tissue, transgenic mouse lines were generated with a human LPL minigene driven by the promoter of the muscle creatine kinase gene, In these mice human LPL was expressed in skeletal muscle and cardiac muscle, but not in other tissues, In proportion to the level of LPL overexpression, decreased plasma triglyceride levels, elevated FFA uptake by muscle tissue, weight loss, and premature death were observed in three independent transgenic mouse lines, The animals developed a severe myopathy characterized by muscle fiber degeneration, fiber atrophy, glycogen storage, and extensive proliferation of mitochondria and pero;uisomes, This degree of proliferation suggests that FFA play an important role in tbe biogenesis of these organelles, Our experiments indicate that LPL is rate limiting for the supply of muscle tissue with triglyceride-derived FFA. Improper regulation of muscle LPL can lead to major pathological changes and may be important in the pathogenesis of some human myopathies. Muscle-specific LPL transgenic mouse lines will serve as a useful animal model for the investigation of myopathies and the biogenesis of mitochondria and peroxisomes.