Department of Medicine, Nephrology Division, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS One. 2013;8(3):e58554. doi: 10.1371/journal.pone.0058554. Epub 2013 Mar 13.
Glucocorticoids production is increased in many pathological conditions that are associated with muscle loss, but their role in causing muscle wasting is not fully understood. We have demonstrated a new mechanism of glucocorticoid-induced muscle atrophy: Dexamethasone (Dex) suppresses satellite cell function contributing to the development of muscle atrophy. Specifically, we found that Dex decreases satellite cell proliferation and differentiation in vitro and in vivo. The mechanism involved Dex-induced upregulation of myostatin and suppression of Akirin1, a promyogenic gene. When myostatin was inhibited in Dex-treated mice, Akirin1 expression increased as did satellite cell activity, muscle regeneration and muscle growth. In addition, silencing myostatin in myoblasts or satellite cells prevented Dex from suppressing Akirin1 expression and cellular proliferation and differentiation. Finally, overexpression of Akirin1 in myoblasts increased their expression of MyoD and myogenin and improved cellular proliferation and differentiation, theses improvements were no longer suppressed by Dex. We conclude that glucocorticoids stimulate myostatin which inhibits Akirin1 expression and the reparative functions of satellite cells. These responses attribute to muscle atrophy. Thus, inhibition of myostatin or increasing Akirin1 expression could lead to therapeutic strategies for improving satellite cell activation and enhancing muscle growth in diseases associated with increased glucocorticoid production.
糖皮质激素的产生在许多与肌肉损失相关的病理条件下增加，但它们在导致肌肉消耗中的作用尚未完全阐明。我们已经证明了糖皮质激素诱导肌肉萎缩的一种新机制：地塞米松（Dex）抑制卫星细胞功能，导致肌肉萎缩的发展。具体而言，我们发现 Dex 可减少体外和体内卫星细胞的增殖和分化。涉及的机制包括 Dex 诱导的肌肉生长抑制素（myostatin）上调和促进肌生成基因 Akirin1 的抑制。当用 Dex 处理的小鼠抑制肌肉生长抑制素时，Akirin1 的表达增加，卫星细胞活性、肌肉再生和肌肉生长增加。此外，在 Dex 处理的成肌细胞或卫星细胞中沉默肌肉生长抑制素可防止 Dex 抑制 Akirin1 的表达以及细胞增殖和分化。最后，在成肌细胞中过表达 Akirin1 增加了它们的 MyoD 和 myogenin 的表达，并改善了细胞增殖和分化，这些改善不再被 Dex 抑制。我们得出结论，糖皮质激素刺激肌肉生长抑制素，抑制 Akirin1 的表达和卫星细胞的修复功能。这些反应归因于肌肉萎缩。因此，抑制肌肉生长抑制素或增加 Akirin1 的表达可能导致治疗策略，以改善与糖皮质激素产生增加相关的疾病中的卫星细胞激活和增强肌肉生长。
