Growth differentiation factor 11 induces skeletal muscle atrophy via a STAT3-dependent mechanism in pulmonary arterial hypertension

IF 5.3 2区医学 Q2 CELL BIOLOGY

Skeletal Muscle Pub Date : 2022-05-06 DOI:10.1186/s13395-022-00292-x

Xiang, Guiling, Ying, Kelu, Jiang, Pan, Jia, Mengping, Sun, Yipeng, Li, Shanqun, Wu, Xiaodan, Hao, Shengyu

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引用次数: 3

Abstract

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.

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生长分化因子11在肺动脉高压中通过stat3依赖机制诱导骨骼肌萎缩

骨骼肌萎缩是肺动脉高压(PAH)的临床显着表型特征，可增加死亡风险。生长分化因子11 (GDF11)在多环芳烃发病机制中起核心作用，在其他情况下对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患者血清GDF11水平升高。mct处理的PAH模型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、fox01和蛋白酶活性)的增加。在体外，GDF11激活STAT3的磷酸化。体外和体内用Stattic拮抗STAT3，可以部分逆转gdf11介导的肌肉萎缩中STAT3/socs3和iNOS/NO等蛋白水解途径。我们的研究结果表明，GDF11有助于肌肉萎缩，抑制其下游分子STAT3有望作为一种治疗干预措施，通过这种干预措施可以直接预防PAH中的肌肉萎缩。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.