一种因腺嘌呤核苷酸转位酶心脏/肌肉同工型缺乏导致的线粒体肌病和心肌病小鼠模型。

A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator.

作者信息

Graham B H, Waymire K G, Cottrell B, Trounce I A, MacGregor G R, Wallace D C

机构信息

Center for Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

出版信息

Nat Genet. 1997 Jul;16(3):226-34. doi: 10.1038/ng0797-226.

DOI:10.1038/ng0797-226

PMID:9207786

Abstract

In an attempt to create an animal model of tissue-specific mitochondrial disease, we generated 'knockout' mice deficient in the heart/muscle isoform of the adenine nucleotide translocator (Ant1). Histological and ultrastructural examination of skeletal muscle from Ant1 null mutants revealed ragged-red muscle fibers and a dramatic proliferation of mitochondria, while examination of the heart revealed cardiac hypertrophy with mitochondrial proliferation. Mitochondria isolated from mutant skeletal muscle exhibited a severe defect in coupled respiration. Ant1 mutant adults also had a resting serum lactate level fourfold higher than that of controls, indicative of metabolic acidosis. Significantly, mutant adults manifested severe exercise intolerance. Therefore, Ant1 mutant mice have the biochemical, histological, metabolic and physiological characteristics of mitochondrial myopathy and cardiomyopathy.

摘要

为了创建一种组织特异性线粒体疾病的动物模型，我们培育出了腺嘌呤核苷酸转位酶（Ant1）心脏/肌肉同工型缺陷的“敲除”小鼠。对Ant1基因敲除突变体的骨骼肌进行组织学和超微结构检查，发现有破碎红肌纤维和线粒体的显著增殖，而对心脏的检查则显示有心肌肥大并伴有线粒体增殖。从突变体骨骼肌中分离出的线粒体在偶联呼吸方面表现出严重缺陷。Ant1突变体成年小鼠的静息血清乳酸水平也比对照组高出四倍，这表明存在代谢性酸中毒。值得注意的是，突变体成年小鼠表现出严重的运动不耐受。因此，Ant1突变小鼠具有线粒体肌病和心肌病的生化、组织学、代谢和生理特征。