Pathophysiological levels of GDF11 activate Smad2/Smad3 signaling and induce muscle atrophy in human iPSC-derived myocytes
Pathophysiological levels of GDF11 activate Smad2/Smad3 signaling and induce muscle atrophy in human iPSC-derived myocytes
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GDF11 的病理生理水平激活 Smad2/Smad3 信号传导并诱导人 iPSC 衍生的肌细胞肌肉萎缩
DOI：
10.1152/ajpcell.00341.2022
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发表时间：
2022
影响因子：
5.5
通讯作者：
Yamauchi Yoshio
中科院分区：
文献类型：
--
作者：
Honda Mikako;Makino Takumi;Zhao Xiaolin;Matsuto Mariko;Sakurai Hidetoshi;Takahashi Yu;Shimizu Makoto;Sato Ryuichiro;Yamauchi Yoshio
几个转化生长因子-β超家族成员对骨骼肌负向调节。肌肉生长抑素(Myostatin，MSTN)是肌肉质量最主要的负性调节因子。最近的研究表明，除了MSTN，GDF11与MSTN有很高的序列同源性，在体外和体内都能在超生理水平诱导肌肉萎缩，但对其作用存在争议。此外，循环中较高的GDF11水平与人类的虚弱有关。另一方面，GDF11的病理生理水平对肌肉萎缩的影响知之甚少。在这里，我们试图确定GDF11的病理生理水平是否足以激活Smad2/Smad3信号并利用人iPSC来源的肌细胞(hiPSC肌细胞)诱导肌肉萎缩。我们首先表明，用病理生理浓度的GDF11孵育HiPSC肌细胞可以显著减少心肌细胞的直径。接下来，我们证明GDF11的病理生理水平足以激活Smad2/3信号。最后，我们发现GDF11的病理生理水平能够诱导促进萎缩的E3泛素连接酶Atrogin-1的表达，FOXO1阻断能够逆转GDF11诱导的Atrogin-1的表达和萎缩表型。综上所述，我们的结果提示GDF11通过GDF11-FOXO1轴在病理生理水平上诱导骨骼肌萎缩。
Skeletal muscle mass is negatively regulated by several TGF-β superfamily members. Myostatin (MSTN) is the most prominent negative regulator of muscle mass. Recent studies show that in addition to MSTN, GDF11, which shares a high sequence identity with MSTN, induces muscle atrophy in vitro and in vivo at supraphysiological levels, whereas controversy regarding its roles exists. Furthermore, higher circulating GDF11 levels associate with frailty in humans. On the other hand, little is known about the effect of pathophysiological levels of GDF11 on muscle atrophy. Here we seek to determine whether pathophysiological levels of GDF11 are sufficient to activate Smad2/Smad3 signaling and induce muscle atrophy using human iPSC-derived myocytes (hiPSC myocytes). We first show that incubating hiPSC myocytes with pathophysiological concentrations of GDF11 significantly reduces myocyte diameters. We next demonstrate that pathophysiological levels of GDF11 are sufficient to activate Smad2/3 signaling. Finally, we show that pathophysiological levels of GDF11 are capable of inducing the expression of Atrogin-1, an atrophy-promoting E3 ubiquitin ligase and that FOXO1 blockage reverses the GDF11-induced Atrogin-1 expression and atrophic phenotype. Collectively, our results suggest that GDF11 induces skeletal muscle atrophy at the pathophysiological levels through the GDF11-FOXO1 axis.