Glucocorticoids and 11β-HSD1 are major regulators of intramyocellular protein metabolism.
Glucocorticoids and 11β-HSD1 are major regulators of intramyocellular protein metabolism.
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DOI：
10.1530/joe-16-0011
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Lavery GG
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文献类型：
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作者：
Morgan SA;Hassan-Smith ZK;Doig CL;Sherlock M;Stewart PM;Lavery GG
处方和内源性糖皮质激素过量的不良代谢作用，即“库欣综合征”，造成显著的健康负担。虽然骨骼肌萎缩和由此产生的肌病是一种临床特征，但这些变化的分子机制尚未完全确定。我们已经表征了糖皮质激素对调节肌肉大小和质量的关键代谢途径和过程的影响，包括：在小鼠C2 C12和人原代肌管培养物中的蛋白质合成、蛋白质降解和成肌细胞增殖。此外，我们还研究了11β-羟基类固醇脱氢酶1（11β-HSD 1）在这些过程中对糖皮质激素可用性的受体前调节作用。皮质酮（CORT）减少小鼠肌管面积，减少蛋白质合成，并增加蛋白质降解。胰岛素样生长因子（IGF 1）mRNA表达降低、哺乳动物雷帕霉素靶蛋白（mTOR）活化磷酸化降低、4 E结合蛋白1（4 E-BP 1）磷酸化降低以及关键萎缩标志物（包括atrogin-1、叉头盒O3 a（FOXO 3a）、肌肉生长抑制素（MSTs）和肌肉环指蛋白-1（MuRF 1））mRNA表达增加支持了这一点。这些发现在人类初级肌管中得到了证实，其中皮质醇也降低了蛋白质合成并增加了蛋白质降解。11-脱氢皮质酮（11 DHC）（在小鼠肌管）和可的松（在人类肌管）对蛋白质代谢的影响是无法区分的CORT/皮质醇治疗。选择性抑制11β-HSD 1可阻断11 DHC/可的松诱导的蛋白质合成减少、蛋白质降解增加和肌管面积减少。此外，CORT/皮质醇，而不是11 DHC/可的松，小鼠和人类成肌细胞增殖能力下降。糖皮质激素是骨骼肌蛋白质稳态和成肌细胞增殖的有效调节剂。我们的数据强调了选择性11β-HSD 1抑制剂在改善与糖皮质激素过量相关的肌肉消耗效应方面的潜在用途。
The adverse metabolic effects of prescribed and endogenous glucocorticoid excess, ‘Cushing’s syndrome’, create a significant health burden. While skeletal muscle atrophy and resultant myopathy is a clinical feature, the molecular mechanisms underpinning these changes are not fully defined. We have characterized the impact of glucocorticoids upon key metabolic pathways and processes regulating muscle size and mass including: protein synthesis, protein degradation, and myoblast proliferation in both murine C2C12 and human primary myotube cultures. Furthermore, we have investigated the role of pre-receptor modulation of glucocorticoid availability by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in these processes. Corticosterone (CORT) decreased myotube area, decreased protein synthesis, and increased protein degradation in murine myotubes. This was supported by decreased mRNA expression of insulin-like growth factor (IGF1), decreased activating phosphorylation of mammalian target of rapamycin (mTOR), decreased phosphorylation of 4E binding protein 1 (4E-BP1), and increased mRNA expression of key atrophy markers including: atrogin-1, forkhead box O3a (FOXO3a), myostatin (MSTN), and muscle-ring finger protein-1 (MuRF1). These findings were endorsed in human primary myotubes, where cortisol also decreased protein synthesis and increased protein degradation. The effects of 11-dehydrocorticosterone (11DHC) (in murine myotubes) and cortisone (in human myotubes) on protein metabolism were indistinguishable from that of CORT/cortisol treatments. Selective 11β-HSD1 inhibition blocked the decrease in protein synthesis, increase in protein degradation, and reduction in myotube area induced by 11DHC/cortisone. Furthermore, CORT/cortisol, but not 11DHC/cortisone, decreased murine and human myoblast proliferative capacity. Glucocorticoids are potent regulators of skeletal muscle protein homeostasis and myoblast proliferation. Our data underscores the potential use of selective 11β-HSD1 inhibitors to ameliorate muscle-wasting effects associated with glucocorticoid excess.