Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
Skelet Muscle. 2022 May 6;12(1):10. doi: 10.1186/s13395-022-00292-x.
Skeletal muscle wasting is a clinically remarkable phenotypic feature of pulmonary arterial hypertension (PAH) that increases the risk of mortality. Growth differentiation factor 11 (GDF11), centrally involved in PAH pathogenesis, has an inhibitory effect on skeletal muscle growth in other conditions. However, whether GDF11 is involved in the pathogenesis of skeletal muscle wasting in PAH remains unknown. We showed that serum GDF11 levels in patients were increased following PAH. Skeletal muscle wasting in the MCT-treated PAH model is accompanied by an increase in circulating GDF11 levels and local catabolic markers (Fbx32, Trim63, Foxo1, and protease activity). In vitro GDF11 activated phosphorylation of STAT3. Antagonizing STAT3, with Stattic, in vitro and in vivo, could partially reverse proteolytic pathways including STAT3/socs3 and iNOS/NO in GDF11-meditated muscle wasting. Our findings demonstrate that GDF11 contributes to muscle wasting and the inhibition of its downstream molecule STAT3 shows promise as a therapeutic intervention by which muscle atrophy may be directly prevented in PAH.
骨骼肌萎缩是肺动脉高压 (PAH) 的一种显著临床表型特征，增加了死亡率。生长分化因子 11 (GDF11) 是 PAH 发病机制中的一个核心因素，它对其他情况下的骨骼肌生长有抑制作用。然而，GDF11 是否参与 PAH 骨骼肌萎缩的发病机制尚不清楚。我们发现，PAH 患者的血清 GDF11 水平升高。MCT 治疗的 PAH 模型中的骨骼肌萎缩伴随着循环 GDF11 水平和局部分解代谢标志物（Fbx32、Trim63、Foxo1 和蛋白酶活性）的增加。GDF11 在体外激活了 STAT3 的磷酸化。在体外和体内使用 Stattic 拮抗 STAT3 可以部分逆转 GDF11 介导的肌肉萎缩中的 STAT3/socs3 和 iNOS/NO 等蛋白水解途径。我们的研究结果表明，GDF11 导致肌肉萎缩，抑制其下游分子 STAT3 可能成为一种治疗干预措施，直接预防 PAH 中的肌肉萎缩。
