A systems approach using Diversity Outbred mice distinguishes the cardiovascular effects and genetics of circulating GDF11 from those of its homolog, myostatin.
A systems approach using Diversity Outbred mice distinguishes the cardiovascular effects and genetics of circulating GDF11 from those of its homolog, myostatin.
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一个系统的方法，使用多样性远交小鼠区分心血管的影响和遗传循环GDF11从它的同系物，肌肉生长抑制素。
DOI：
10.1093/g3journal/jkab293
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发表时间：
2021-10-19
期刊：
影响因子：
--
通讯作者：
Pazdro R
中科院分区：
文献类型：
--
作者：
Starcher AE;Peissig K;Stanton JB;Churchill GA;Cai D;Maxwell JT;Grider A;Love K;Chen SY;Coleman AE;Strauss E;Pazdro R
生长分化因子11（GDF 11）是TGF-β蛋白家族的成员，与心肌肥大的发生有关。虽然一些研究表明，全身性GDF 11可以防止心肌细胞扩大和左心室壁增厚，但GDF 11的真正影响以及其所谓的作用是否实际上归因于其同系物肌肉生长抑制素仍然存在不确定性。进行本研究以解析人类遗传学的小鼠模型（Diversity Outbred（DO）原种）中GDF 11、肌肉生长抑制素和心脏肥大之间的统计学和遗传学关系。在DO人群中，血清GDF 11浓度与心肌细胞横截面积呈正相关，而循环肌肉生长抑制素水平与体重、心脏重量和左心室壁厚度和质量呈负相关。遗传分析显示，血清GDF 11浓度具有适度遗传性（0.23），并在小鼠3号染色体上发现了一个提示性峰，该峰与基因Hey 1（一种转录抑制因子）非常接近。生物信息学分析定位了小鼠和人类基因组中Gdf 11基因上游HEY 1蛋白的假定结合位点。相比之下，血清肌肉生长抑制素浓度比GDF 11浓度更具有遗传性（0.57），并且映射确定了基因FoxO 1附近的重要位点，该基因FoxO 1在人类和小鼠肌肉生长抑制素基因的启动子区域内具有结合基序。总之，这些发现更精确地定义了GDF 11和肌肉生长抑制素的独立心血管作用，以及它们不同的调控途径。Hey 1是GDF 11调控的一个令人信服的候选者，并将在未来的研究中进一步评估。
Growth differentiation factor 11 (GDF11) is a member of the TGF-β protein family that has been implicated in the development of cardiac hypertrophy. While some studies have suggested that systemic GDF11 protects against cardiomyocyte enlargement and left ventricular wall thickening, there remains uncertainty about the true impact of GDF11 and whether its purported effects are actually attributable to its homolog myostatin. This study was conducted to resolve the statistical and genetic relationships among GDF11, myostatin, and cardiac hypertrophy in a mouse model of human genetics, the Diversity Outbred (DO) stock. In the DO population, serum GDF11 concentrations positively correlated with cardiomyocyte cross-sectional area, while circulating myostatin levels were negatively correlated with body weight, heart weight, and left ventricular wall thickness and mass. Genetic analyses revealed that serum GDF11 concentrations are modestly heritable (0.23) and identified a suggestive peak on murine chromosome 3 in close proximity to the gene Hey1, a transcriptional repressor. Bioinformatic analyses located putative binding sites for the HEY1 protein upstream of the Gdf11 gene in the mouse and human genomes. In contrast, serum myostatin concentrations were more heritable (0.57) than GDF11 concentrations, and mapping identified a significant locus near the gene FoxO1, which has binding motifs within the promoter regions of human and mouse myostatin genes. Together, these findings more precisely define the independent cardiovascular effects of GDF11 and myostatin, as well as their distinct regulatory pathways. Hey1 is a compelling candidate for the regulation of GDF11 and will be further evaluated in future studies.