Honda Mikako, Makino Takumi, Zhao Xiaolin, Matsuto Mariko, Sakurai Hidetoshi, Takahashi Yu, Shimizu Makoto, Sato Ryuichiro, Yamauchi Yoshio
Laboratory of Food Biochemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
Am J Physiol Cell Physiol. 2022 Nov 1;323(5):C1402-C1409. doi: 10.1152/ajpcell.00341.2022. Epub 2022 Sep 12.
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.
骨骼肌质量受到几种转化生长因子-β（TGF-β）超家族成员的负调控。肌肉生长抑制素（MSTN）是肌肉质量最主要的负调控因子。最近的研究表明，除MSTN外，与MSTN具有高度序列同一性的生长分化因子11（GDF11）在体外和体内超生理水平时会诱导肌肉萎缩，但其作用仍存在争议。此外，循环中较高水平的GDF11与人类身体虚弱有关。另一方面，关于GDF11的病理生理水平对肌肉萎缩的影响知之甚少。在这里，我们试图利用人诱导多能干细胞衍生的心肌细胞（hiPSC心肌细胞）来确定GDF11的病理生理水平是否足以激活Smad2/Smad3信号传导并诱导肌肉萎缩。我们首先表明，用病理生理浓度的GDF11孵育hiPSC心肌细胞会显著降低心肌细胞直径。接下来我们证明，GDF11 的病理生理水平足以激活Smad2/3信号传导。最后，我们表明，GDF11的病理生理水平能够诱导Atrogin-1的表达，Atrogin-1是一种促进萎缩的E3泛素连接酶，并且FOXO1的阻断可逆转GDF11诱导的Atrogin-1表达和萎缩表型。总的来说，我们的结果表明，GDF11在病理生理水平通过GDF11-FOXO1轴诱导骨骼肌萎缩。
