Patel Mehul S, Lee Jen, Baz Manuel, Wells Claire E, Bloch Susannah, Lewis Amy, Donaldson Anna V, Garfield Benjamin E, Hopkinson Nicholas S, Natanek Amanda, Man William D-C, Wells Dominic J, Baker Emma H, Polkey Michael I, Kemp Paul R
NIHR Respiratory Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust and Imperial College London UK.
Section of Molecular Medicine National Heart and Lung Institute, Imperial College London London UK.
J Cachexia Sarcopenia Muscle. 2016 Sep;7(4):436-48. doi: 10.1002/jcsm.12096. Epub 2015 Dec 29.
Loss of muscle mass is a co-morbidity common to a range of chronic diseases including chronic obstructive pulmonary disease (COPD). Several systemic features of COPD including increased inflammatory signalling, oxidative stress, and hypoxia are known to increase the expression of growth differentiation factor-15 (GDF-15), a protein associated with muscle wasting in other diseases. We therefore hypothesized that GDF-15 may contribute to muscle wasting in COPD.
We determined the expression of GDF-15 in the serum and muscle of patients with COPD and analysed the association of GDF-15 expression with muscle mass and exercise performance. To determine whether GDF-15 had a direct effect on muscle, we also determined the effect of increased GDF-15 expression on the tibialis anterior of mice by electroporation.
Growth differentiation factor-15 was increased in the circulation and muscle of COPD patients compared with controls. Circulating GDF-15 was inversely correlated with rectus femoris cross-sectional area (P < 0.001) and exercise capacity (P < 0.001) in two separate cohorts of patients but was not associated with body mass index. GDF-15 levels were associated with 8-oxo-dG in the circulation of patients consistent with a role for oxidative stress in the production of this protein. Local over-expression of GDF-15 in mice caused wasting of the tibialis anterior muscle that expressed it but not in the contralateral muscle suggesting a direct effect of GDF-15 on muscle mass (P < 0.001).
Together, the data suggest that GDF-15 contributes to the loss of muscle mass in COPD.
肌肉量减少是包括慢性阻塞性肺疾病（COPD）在内的一系列慢性疾病常见的合并症。已知COPD的几种全身特征，包括炎症信号增强、氧化应激和缺氧，会增加生长分化因子15（GDF - 15）的表达，GDF - 15是一种在其他疾病中与肌肉萎缩相关的蛋白质。因此，我们推测GDF - 15可能导致COPD患者的肌肉萎缩。
我们测定了COPD患者血清和肌肉中GDF - 15的表达，并分析了GDF - 15表达与肌肉量和运动表现之间的关联。为了确定GDF - 15是否对肌肉有直接作用，我们还通过电穿孔法测定了GDF - 15表达增加对小鼠胫前肌的影响。
与对照组相比，COPD患者循环系统和肌肉中的生长分化因子15增加。在两个独立的患者队列中，循环中的GDF - 15与股直肌横截面积（P < 0.001）和运动能力（P < 0.001）呈负相关，但与体重指数无关。患者循环中的GDF - 15水平与8 - 氧代 - dG相关，这表明氧化应激在该蛋白产生中起作用。小鼠局部过表达GDF - 15导致表达该蛋白的胫前肌萎缩，但对侧肌肉未出现萎缩，提示GDF - 15对肌肉量有直接影响（P < 0.001）。
总体而言，数据表明GDF - 15导致COPD患者肌肉量减少。
