Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Endocrinology. 2010 Aug;151(8):3706-19. doi: 10.1210/en.2010-0150. Epub 2010 Jun 9.
Glucocorticoids are the most widely used antiinflammatory drugs in the world. However, prolonged use of glucocorticoids results in undesirable side effects such as muscle wasting, osteoporosis, and diabetes. Skeletal muscle wasting, which currently has no approved therapy, is a debilitating condition resulting from either reduced muscle protein synthesis or increased degradation. The imbalance in protein synthesis could occur from increased expression and function of muscle-specific ubiquitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle ring finger 1 (MuRF1), or decreased function of the IGF-I and phosphatidylinositol-3 kinase/Akt kinase pathways. We examined the effects of a nonsteroidal tissue selective androgen receptor modulator (SARM) and testosterone on glucocorticoid-induced muscle atrophy and castration-induced muscle atrophy. The SARM and testosterone propionate blocked the dexamethasone-induced dephosphorylation of Akt and other proteins involved in protein synthesis, including Forkhead box O (FoxO). Dexamethasone caused a significant up-regulation in the expression of ubiquitin ligases, but testosterone propionate and SARM administration blocked this effect by phosphorylating FoxO. Castration induced rapid myopathy of the levator ani muscle, accompanied by up-regulation of MAFbx and MuRF1 and down-regulation of IGF-I, all of which was attenuated by a SARM. The results suggest that levator ani atrophy caused by hypogonadism may be the result of loss of IGF-I stimulation, whereas that caused by glucocorticoid treatment relies almost solely on up-regulation of MAFbx and MuRF1. Our studies provide the first evidence that glucocorticoid- and hypogonadism-induced muscle atrophy are mediated by distinct but overlapping mechanisms and that SARMs may provide a more effective and selective pharmacological approach to prevent glucocorticoid-induced muscle loss than steroidal androgen therapy.
糖皮质激素是世界上应用最广泛的抗炎药物。然而，长期使用糖皮质激素会导致不良的副作用，如肌肉减少症、骨质疏松症和糖尿病。目前尚无批准的治疗方法的骨骼肌减少症是一种衰弱状态，是由于肌肉蛋白合成减少或降解增加引起的。蛋白质合成的不平衡可能是由于肌肉特异性泛素连接酶、肌肉萎缩 F 盒（MAFbx）/肌萎缩蛋白 1（MuRF1）的表达和功能增加，或 IGF-I 和磷脂酰肌醇-3 激酶/Akt 激酶途径的功能降低引起的。我们研究了非甾体组织选择性雄激素受体调节剂（SARM）和睾酮对糖皮质激素诱导的肌肉萎缩和去势诱导的肌肉萎缩的影响。SARM 和丙酸睾酮阻断了地塞米松诱导的 Akt 和其他参与蛋白质合成的蛋白的去磷酸化，包括 Forkhead box O（FoxO）。地塞米松导致泛素连接酶的表达显著上调，但睾酮丙酸酯和 SARM 给药通过磷酸化 FoxO 阻断了这种作用。去势导致提肛肌迅速发生肌病，同时 MAFbx 和 MuRF1 的表达上调，IGF-I 的表达下调，这些都被 SARM 减轻了。结果表明，去势引起的提肛肌萎缩可能是 IGF-I 刺激丧失的结果，而糖皮质激素治疗引起的提肛肌萎缩几乎完全依赖于 MAFbx 和 MuRF1 的上调。我们的研究首次提供了证据表明，糖皮质激素和去势引起的肌肉萎缩是由不同但重叠的机制介导的，SARM 可能为预防糖皮质激素引起的肌肉损失提供一种比甾体雄激素治疗更有效和更具选择性的药理学方法。
