期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 323, 期 5, 页码 C1402-C1409出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00341.2022
关键词
GDF11; human iPSCs; muscle atrophy; myostatin; skeletal muscle
资金
- KAKENHI from the Japan Society for the Promotion of Science [19H02908, 19K22270, 20H00408]
- Tojuro Iijima Foundation for Food Science and Technology
- Japan Food Chemical Research Foundation
This study found that GDF11 induces muscle atrophy through the GDF11-FOXO1 axis at pathophysiological levels. Using human iPSC-derived myocytes, researchers demonstrated that pathophysiological concentrations of GDF11 significantly reduce myocyte diameters and activate the Smad2/3 signaling pathway.
Skeletal muscle mass is negatively regulated by several TGF-8 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-promot-ing 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据