Effects of a Novel Selective Androgen Receptor Modulator on Dexamethasone-Induced and Hypogonadism-Induced Muscle Atrophy
Effects of a Novel Selective Androgen Receptor Modulator on Dexamethasone-Induced and Hypogonadism-Induced Muscle Atrophy
复制标题
DOI：
10.1210/en.2010-0150
复制
发表时间：
2010-08-01
期刊：
影响因子：
4.8
通讯作者：
Dalton, James T.
中科院分区：
文献类型：
--
作者：
Jones, Amanda;Hwang, Dong-Jin;Dalton, James T.
糖皮质激素是世界上使用最广泛的抗肿瘤药物。然而，长期使用糖皮质激素会导致不良副作用，如肌肉萎缩、骨质疏松症和糖尿病。骨骼肌萎缩，目前还没有批准的治疗，是一种衰弱的条件，导致减少肌肉蛋白质合成或增加降解。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）/atrogin-1和肌肉环指蛋白1（MuRF 1）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。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和丙酸睾酮阻止了地塞米松诱导的Akt和其他参与蛋白质合成的蛋白质（包括Forkhead boxO（FoxO））的去磷酸化。地塞米松引起泛素连接酶表达的显著上调，但丙酸睾酮和SARM给药通过磷酸化FoxO阻断了这种作用。去势诱导肛提肌的快速肌病，伴随MAFbx和MuRF 1的上调和IGF-I的下调，所有这些都被SARM减弱。结果表明，由性腺功能减退引起的肛提肌萎缩可能是IGF-I刺激丧失的结果，而糖皮质激素治疗引起的肛提肌萎缩几乎完全依赖于MAFbx和MuRF 1的上调。我们的研究提供了第一个证据，表明糖皮质激素和性腺功能减退诱导的肌肉萎缩是由不同但重叠的机制介导的，并且SARM可能提供比类固醇雄激素治疗更有效和选择性的药理学方法来预防糖皮质激素诱导的肌肉损失。（内分泌学151：3706-3719，2010）
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 boxO (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. (Endocrinology 151: 3706-3719, 2010)