Effects of mtDNA in SHR-mtF344 versus SHR conplastic strains on reduced OXPHOS enzyme levels, insulin resistance, cardiac hypertrophy, and systolic dysfunction
Effects of mtDNA in SHR-mtF344 versus SHR conplastic strains on reduced OXPHOS enzyme levels, insulin resistance, cardiac hypertrophy, and systolic dysfunction
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DOI：
10.1152/physiolgenomics.00069.2014
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发表时间：
2014-09-15
影响因子：
4.6
通讯作者：
Pravenec, Michal
中科院分区：
文献类型：
--
作者：
Houstek, Josef;Vrbacky, Marek;Pravenec, Michal
常见的近交系实验大鼠可分为四个主要的线粒体DNA（mtDNA）单倍型组，代表BN，F344，LEW和SHR品系。在本研究中，我们通过比较SHR与SHR-mt（F344）共塑株（除了线粒体基因组外，它们在遗传上是相同的），研究了SHR与F344 mtDNA的代谢和血液动力学效应。与SHR相比，F344 mtDNA蛋白质编码基因发生了13个氨基酸替换，tRNA基因发生了7个单核苷酸多态性，rRNA基因发生了12个单核苷酸变异。心脏左心室（LV），肌肉和肝脏中的氧化磷酸化系统（OXPHOS）的分析显示，与SHR品系相比，SHR-mt（F344）Conplastic大鼠中的几种呼吸链复合物的活性和含量降低。保变大鼠左室OXPHOS功能降低与心室相对质量显著增加和心室短轴缩短率显著降低相关，但与血压无关。此外，Conplastic大鼠骨骼肌对胰岛素作用的敏感性降低，葡萄糖耐量受损。这些结果提供了证据，线粒体基因组的遗传性改变，在核基因组和其他混杂因素的变化的情况下，易患胰岛素抵抗，心脏肥大和收缩功能障碍。
Common inbred strains of the laboratory rat can be divided into four major mitochondrial DNA (mtDNA) haplotype groups represented by the BN, F344, LEW, and SHR strains. In the current study, we investigated the metabolic and hemodynamic effects of the SHR vs. F344 mtDNA by comparing the SHR vs. SHR-mt(F344) conplastic strains that are genetically identical except for their mitochondrial genomes. Altogether 13 amino acid substitutions in protein coding genes, seven single nucleotide polymorphisms in tRNA genes, and 12 single nucleotide changes in rRNA genes were detected in F344 mtDNA compared with SHR mtDNA. Analysis of oxidative phosphorylation system (OXPHOS) in heart left ventricles (LV), muscle, and liver revealed reduced activity and content of several respiratory chain complexes in SHR-mt(F344) conplastic rats compared with the SHR strain. Lower function of OXPHOS in LV of conplastic rats was associated with significantly increased relative ventricular mass and reduced fractional shortening that was independent of blood pressure. In addition, conplastic rats exhibited reduced sensitivity of skeletal muscles to insulin action and impaired glucose tolerance. These results provide evidence that inherited alterations in mitochondrial genome, in the absence of variation in the nuclear genome and other confounding factors, predispose to insulin resistance, cardiac hypertrophy and systolic dysfunction.