Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension
Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension
复制标题
DOI：
10.1136/thoraxjnl-2017-211440
复制
发表时间：
2019-02-01
期刊：
影响因子：
10
通讯作者：
Kemp, Paul R.
中科院分区：
文献类型：
--
作者：
Garfield, Benjamin E.;Crosby, Alexi;Kemp, Paul R.
前言骨骼肌功能障碍是肺动脉高压（PAH）的重要临床并发症。生长/分化因子15（GDF-15）是PAH的预后标志物，与其他疾病中的肌肉损失相关。我们的目的是定义协会的GDF-15和肌肉萎缩的PAH，评估其效用作为一个生物标志物的肌肉损失，并探讨其下游信号通路作为一个治疗target.Methods GDF-15水平和措施的肌肉大小和强度进行了分析，在野百合碱（MCT）大鼠，Sugen/缺氧小鼠和30例PAH患者。在C2 C12肌管中，鉴定了GDF-15的下游靶标。结果在MCT大鼠中，循环GDF-15水平与胫骨前肌（TA）肌纤维直径相关（Pearson r=-0.61，p =0.003）。PAH患者的血浆GDF-15水平≥ 80%。在体外，GDF-15刺激TGF β激活的激酶1（TAK 1）磷酸化的增加。在体外和体内用5（Z）-7-oxozeaenol拮抗TA K1导致C2 C12细胞和继续生长的动物的TA中纤维直径增加和atrogin-1的mRNA表达减少。循环GDF-15水平也减少了那些动物响应treatment.Conclusions循环GDF-15是一个生物标志物的肌肉损失PAH是响应于治疗。TA K1抑制显示出作为可直接预防PAH中肌肉萎缩的方法的前景。
Introduction Skeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target.Methods GDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo.Results Circulating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=-0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of = 80%. In vitro GDF-15 stimulated an increase in phosphorylation of TGF beta-activated kinase 1 (TAK1). Antagonising TA K1, with 5(Z)-7-oxozeaenol, in vitro and in vivo led to an increase in fibre diameter and a reduction in mRNA expression of atrogin-1 in both C2C12 cells and in the TA of animals who continued to grow. Circulating GDF-15 levels were also reduced in those animals which responded to treatment.Conclusions Circulating GDF-15 is a biomarker of muscle loss in PAH that is responsive to treatment. TA K1 inhibition shows promise as a method by which muscle atrophy may be directly prevented in PAH.