Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.

中文翻译：

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单核二倍体心肌细胞的频率是心脏再生自然变化的基础。

成年哺乳动物心肌细胞在受伤后的再生被认为是微乎其微的。单核二倍体心肌细胞 (MNDCM) 是成人心脏中相对较小的亚群，可能是观察到的再生程度的原因，但这尚未经过测试。我们调查了 120 个近交小鼠品系，发现成年单核心肌细胞的频率变化惊人（> 7 倍）。冠状动脉结扎后心肌细胞增殖和心脏功能恢复均与损伤前 MNDCM 含量相关。使用全基因组关联，我们将 Tnni3k 鉴定为影响该成分变异的一个基因，并证明 Tnni3k 敲除导致 MNDCM 含量升高和损伤后心肌细胞增殖增加。反过来，斑马鱼中 Tnni3k 的过表达促进心肌细胞多倍体化并损害心脏再生。我们的结果证实了 MNDCM 在心脏再生中的相关性。此外，它们暗示内在心脏再生在所有个体中都不是有限的或统一的，而是受多个基因影响的可变特征。