Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency
Tnni3k alleles influence ventricular mononuclear diploid cardiomyocyte frequency
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DOI：
10.1371/journal.pgen.1008354
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发表时间：
2019-10-01
期刊：
影响因子：
4.5
通讯作者：
Sucov, Henry M.
中科院分区：
文献类型：
--
作者：
Gan, Peiheng;Patterson, Michaela;Sucov, Henry M.
最近的证据表明单核二倍体心肌细胞是出生后心脏的增殖和再生亚群。这些心肌细胞的数量是一个复杂的性状，显示出基于多个多态性基因的组合影响的近交系小鼠品系之间的实质性自然变异。一个被证实影响该参数的基因是心肌细胞特异性激酶Tnni 3 k。在这里，我们研究了许多物种的Tnni 3 k等位基因。在小鼠中使用新产生的激酶死亡等位基因，我们表明Tnni 3 k功能依赖于其激酶活性。在体外激酶试验中，我们发现几种常见的人TNNI 3 K激酶结构域变体基本上损害了激酶活性，表明TNNI 3 K可能影响人类心脏再生能力，也可能影响人类心脏病的其他方面。我们发现，两个激酶结构域移码突变在小鼠中引起的无义介导的衰变的功能丧失的后果。我们进一步表明，Tnni 3 k基因在两个物种的鼹鼠，大鼠已独立地演变成一个假基因，推测与这些物种的过渡到一个低代谢和缺氧的地下生活。这可以通过观察到小鼠中的Tnni 3 k功能与氧化应激会聚以调节单核二倍体心肌细胞频率来解释。与其他研究的啮齿动物不同，裸鼹鼠具有令人惊讶的高（30%）单核心肌细胞水平，但它们的大多数单核心肌细胞是多倍体;它们的单核二倍体心肌细胞水平（7%）在近交系小鼠品系的已知范围（2-10%）内。裸鼹鼠提供了进一步的见解，最近的建议，心肌细胞多倍性与进化收购的恒温。
Recent evidence implicates mononuclear diploid cardiomyocytes as a proliferative and regenerative subpopulation of the postnatal heart. The number of these cardiomyocytes is a complex trait showing substantial natural variation among inbred mouse strains based on the combined influences of multiple polymorphic genes. One gene confirmed to influence this parameter is the cardiomyocyte-specific kinase Tnni3k. Here, we have studied Tnni3k alleles across a number of species. Using a newly-generated kinase-dead allele in mice, we show that Tnni3k function is dependent on its kinase activity. In an in vitro kinase assay, we show that several common human TNNI3K kinase domain variants substantially compromise kinase activity, suggesting that TNNI3K may influence human heart regenerative capacity and potentially also other aspects of human heart disease. We show that two kinase domain frameshift mutations in mice cause loss-of-function consequences by nonsense-mediated decay. We further show that the Tnni3k gene in two species of mole-rat has independently devolved into a pseudogene, presumably associated with the transition of these species to a low metabolism and hypoxic subterranean life. This may be explained by the observation that Tnni3k function in mice converges with oxidative stress to regulate mononuclear diploid cardiomyocyte frequency. Unlike other studied rodents, naked mole-rats have a surprisingly high (30%) mononuclear cardiomyocyte level but most of their mononuclear cardiomyocytes are polyploid; their mononuclear diploid cardiomyocyte level (7%) is within the known range (2-10%) of inbred mouse strains. Naked mole-rats provide further insight on a recent proposal that cardiomyocyte polyploidy is associated with evolutionary acquisition of endothermy.