The role of transforming growth factor beta superfamily members in the pathogenesis of muscle weakness associated with pulmonary arterial hypertension

肺动脉高压（PAH）是一种导致从肺部获取氧气的血管血压升高的疾病。它的预期寿命与一些晚期常见癌症相似。有治疗方法，但没有治愈方法。我们现在知道PAH与腿部肌肉无力有关，这有助于患者出现症状。康复可以提高患者的运动能力，逆转他们肌肉细胞中的变化，这一点也越来越清楚。这些课程可以提高生活质量，并可能延长人们的寿命。研究人员认为，在患有其他慢性疾病的患者血液中发现的高水平的某些蛋白质会影响肌肉功能和生长。其中一种蛋白质被称为生长分化因子（GDF）8，高水平的GDF与COPD和心力衰竭（HF）中的肌无力有关。有趣的是，有一些药物可以阻断GDF-8对肌肉细胞的作用，这在动物中已经显示出导致肌肉尺寸增加。一种称为GDF-15的相关蛋白质在PAH患者中水平升高，并与预后有关。我们开始研究GDF-15在肌肉无力发展中的作用。在COPD患者和健康志愿者中，我们发现随着GDF-15水平的上升，肌肉力量下降。我们还发现，血液中的GDF-15水平在心脏手术后保持高水平，只有在大腿肌肉尺寸损失超过10%的患者中。此外，我们发现GDF-15改变肌肉力量和大小的机制与GDF-8相同。最后，当我们将GDF-15添加到肌肉细胞中时，它们变得更小。我们认为这些初步结果表明，GDF-15可能是导致PAH肌无力的重要蛋白质，它可能通过与GDF-8相同的机制起作用。我们的目标是通过找出GDF-15产生的位置以及它是否与PAH动物模型中的肌肉无力相关来测试这一理论。我们希望发现当我们加入GDF-15和可能阻止其作用于肌肉细胞的药物时会发生什么，并找出PAH患者血液和肌肉中的GDF-15水平是否参与肌肉无力的发展这项研究将由伦敦帝国理工学院肌肉无力和PAH领域的多位专家监督下的一名博士生进行。我们将采取肺动脉高压大鼠和小鼠的组织，并检查GDF-15的产生部位。我们将采取这些动物的肌肉组织，并分析它们，看看这些蛋白质在肌肉中的水平是否与虚弱有关。接下来，我们将尝试定义这些蛋白质对肌肉细胞的影响，并找出它们如何引起这些影响。我们将首先在实验室中向生长的肌肉细胞中添加蛋白质，然后使用药物阻断它们的作用，这可能会阻止GDF-15与这些细胞结合。接下来，我们将添加基因，导致小鼠肌肉中GDF-15的产量增加。一旦我们确定这会导致肌肉无力，我们将尝试通过添加更多的基因来阻止它们的作用，这些基因会导致蛋白质的释放，从而阻止GDF-15与肌肉细胞结合。最后，我们将研究PAH患者血液中GDF-15的水平，以确定这些是否与肌无力有关。我们还将对允许我们的患者进行肌肉活检，以便我们可以检查GDF-15可能导致患有PAH的男性和女性肌肉无力的方式。我们预计这项工作将有助于更好地了解GDF-15在PAH患者肌肉无力中的作用。此外，GDF-15水平可能对我们确定哪些患者患有肌无力很重要。我们希望在未来进行临床试验的药物，阻止GDF-15的行动。

Pulmonary arterial hypertension (PAH) is a disease that causes raised blood pressure in blood vessels that pick up oxygen from the lungs. It has a life expectancy similar to some advanced, common cancers. There is treatment available but there is no cure. We now know that PAH is associated with weakness in the muscles in the legs, which contributes to the symptoms that patients experience. It is also becoming clear that rehabilitation can improve patients exercise capacity and reverses the changes seen in their muscle cells. These classes can improve quality of life and may prolong people's lives. Researchers believe that certain proteins found in high levels in the blood of patients with other chronic diseases can affect muscle function and growth. One of these proteins is called growth differentiating factor (GDF) 8, high levels of which are associated with muscle weakness in COPD and heart failure (HF). Interestingly there are drugs available which block the actions of GDF-8 on muscle cells which has been shown in animals to result in increased muscle size. A related protein called GDF-15 is found in elevated levels in patients with PAH, and is linked to prognosis. We started investigating the role of GDF-15 in the development of muscle weakness. In patients with COPD as well as healthy volunteers we found that as GDF-15 levels went up, muscle strength went down. We also found that GDF-15 levels in the blood stayed high after heart surgery only in patients who lost more than about 10% of their thigh muscle size. Furthermore we showed that the mechanism through which GDF-15 changes muscle strength and size is the same as that seen in GDF-8. Finally when we added GDF-15 to muscle cells they became smaller. We believe these preliminary results suggest that GDF-15 may be an important protein in causing muscle weakness in PAH and that it may act through the same mechanisms as GDF-8. We aim to test this theory by finding out where GDF-15 is produced and whether it is associated with muscle weakness in animal models of PAH. We want to discover what happens when we add GDF-15 and drugs that may block its actions to muscle cells, and to find out whether GDF-15 levels in the blood and muscles of patients with PAH are involved in the development of muscle weaknessThe research will be carried out by a PhD student under the supervision of a number of experts in the field of muscle weakness and PAH at Imperial College London. We will take the tissue of rats and mice with pulmonary hypertension and examine where GDF-15 is produced. We will take the muscle tissue of these animals and analyze them to see the whether the levels of these proteins in the muscle is related with weakness. Next we will try and define the effects of these proteins on muscle cells and find out how they cause these effects. We will do this first by adding proteins to growing muscle cells in the lab and then blocking their actions using drugs which may stop GDF-15 binding to these cells. Next we will add genes, which cause increased production of GDF-15 to the muscles of mice. Once we establish that this results in muscle weakness we will try to block their actions by adding further genes which cause release of proteins that stop GDF-15 binding to muscle cells. Finally we will investigate the levels of GDF-15 in the blood of patients with PAH to see whether these are related to muscle weakness. We will also take muscle biopsies from the patients who allow us to, in order that we can examine the way in which GDF-15 may cause muscle weakness in men and women with PAH.We expect this work will lead to a greater understanding of the role of GDF-15 in muscle weakness in patients with PAH. IN addition GDF-15 levels may be important in allowing us to define which patients have muscle weakness. We hope in the future to perform a clinical trial of drugs which block the actions of GDF-15.