Circulating Growth Differentiation Factor 11/8 Levels Decline With Age.
Circulating Growth Differentiation Factor 11/8 Levels Decline With Age.
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DOI：
10.1161/circresaha.115.307521
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发表时间：
2016-01-08
影响因子：
20.1
通讯作者：
Lee RT
中科院分区：
文献类型：
--
作者：
Poggioli T;Vujic A;Yang P;Macias-Trevino C;Uygur A;Loffredo FS;Pancoast JR;Cho M;Goldstein J;Tandias RM;Gonzalez E;Walker RG;Thompson TB;Wagers AJ;Fong YW;Lee RT
生长分化因子11（GDF 11）和GDF 8是转化生长因子β超家族的成员，具有89%的蛋白质序列同源性。我们之前已经表明，小鼠的循环GDF 11水平随着年龄的增长而下降。然而，Egerman等人最近的一项研究报道，小鼠血清中的GDF 11/8水平随着年龄的增长而增加。在这里，我们阐明了循环GDF 11/8水平随年龄变化的方向，并研究了GDF 11给药对小鼠心脏的影响。我们验证了我们先前的发现，即GDF 11/8的循环水平在小鼠、大鼠、马和绵羊中随着年龄的增长而下降。此外，我们通过Western分析表明，如Egerman等人所报道的，GDF 11水平的明显年龄依赖性增加可归因于抗GDF 11抗体与免疫球蛋白的交叉反应性，已知其随年龄增加。在小鼠中给予GDF 11在体内迅速激活心肌中的SMAD 2和SMAD 3信号传导，并且仅在9天后以剂量依赖性方式降低年轻（2月龄）和老年（22月龄）小鼠的心脏质量。我们的研究证实了多种哺乳动物血清GDF 11/8水平的年龄依赖性下降，并且外源性GDF 11快速激活SMAD信号传导并减小心肌细胞大小。揭开GDF 11/8年龄依赖性下降的分子基础可以深入了解年龄依赖性心脏病理学。
Growth differentiation factor 11 (GDF11) and GDF8 are members of the transforming growth factor-β superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al reported that GDF11/8 levels increase with age in mouse serum. Here, we clarify the direction of change of circulating GDF11/8 levels with age and investigate the effects of GDF11 administration on the murine heart. We validated our previous finding that circulating levels of GDF11/8 decline with age in mice, rats, horses, and sheep. Furthermore, we showed by Western analysis that the apparent age-dependent increase in GDF11 levels, as reported by Egerman et al, is attributable to cross-reactivity of the anti-GDF11 antibody with immunoglobulin, which is known to increase with age. GDF11 administration in mice rapidly activated SMAD2 and SMAD3 signaling in myocardium in vivo and decreased cardiac mass in both young (2-month-old) and old (22-month-old) mice in a dose-dependent manner after only 9 days. Our study confirms an age-dependent decline in serum GDF11/8 levels in multiple mammalian species and that exogenous GDF11 rapidly activates SMAD signaling and reduces cardiomyocyte size. Unraveling the molecular basis for the age-dependent decline in GDF11/8 could yield insight into age-dependent cardiac pathologies.