Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
J Appl Physiol (1985). 2013 May;114(9):1329-39. doi: 10.1152/japplphysiol.00503.2012. Epub 2012 Aug 30.
Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts.
肌肉减少与慢性阻塞性肺疾病（COPD）的预后不良有关。运动可以刺激肌肉恢复，但效果因临床状况和药物治疗而异。全身糖皮质激素，通常在急性疾病加重时大剂量使用，或在终末期疾病中作为维持治疗，已知会导致肌肉减少。由于肌肉质量的恢复涉及胰岛素样生长因子（IGF）-I 信号，而合成代谢类固醇可以刺激该信号，因此研究了糖皮质激素和同时使用合成代谢类固醇刺激 IGF-I 对肌肉恢复和生长的影响。评估了糖皮质激素和 IGF-I 信号对分化的 C2C12 肌母细胞生长的影响及其相互作用。作为原理验证，我们对一项临床试验进行了事后分析，该试验研究了合成代谢类固醇补充对 COPD 肌肉减少患者肌肉恢复的疗效，并对使用糖皮质激素的患者进行了分层。糖皮质激素强烈抑制蛋白质合成信号、肌管形成和肌肉特异性蛋白表达。相比之下，在糖皮质激素存在的情况下，IGF-I 协同刺激肌管融合和肌原纤维蛋白表达，这与 IGF-I 恢复蛋白质合成信号以及糖皮质激素增加肌肉特异性基因的转录激活相对应。在接受维持性糖皮质激素治疗的 COPD 患者中，临床试验还揭示了合成代谢类固醇对肌肉质量和呼吸肌力量的增强作用。总之，合成代谢类固醇和糖皮质激素对肌肉恢复的协同作用可能是由于糖皮质激素对蛋白质合成信号的抑制作用得到缓解，从而允许有效翻译糖皮质激素诱导的肌肉特异性基因转录物的积累。
