Targeting the myostatin signaling pathway to treat muscle wasting diseases.
Targeting the myostatin signaling pathway to treat muscle wasting diseases.
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DOI：
10.1097/spc.0b013e32834bddf9
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发表时间：
2011-12-01
影响因子：
2.1
通讯作者：
Mitch, William E
中科院分区：
文献类型：
--
作者：
Han, H Q;Mitch, William E
综述的目的：了解肌肉萎缩的机制以及抑制肌肉生长抑制素信号传导如何影响肌肉萎缩。最近发现：肌生长抑制素信号对于理解肌肉萎缩的发病机制至关重要，因为阻断信号可以减轻啮齿动物分解代谢疾病（包括癌症、慢性肾衰竭或心力衰竭）的肌肉损失。摘要：肌肉萎缩增加了发病率和死亡率的风险。但是，估计肌肉萎缩程度的可靠性是有争议的，就像恶病质等术语的定义一样。关于肌肉萎缩的病理生理学，包括泛素-蛋白酶体系统（UPS）的主要作用，它与其他蛋白酶一起降解蛋白质并限制蛋白质合成。相比之下，很少有成功的扭转肌肉损失的策略被测试过。几种分解代谢条件的特征是炎症，糖皮质激素产生增加，以及胰岛素和IGF-1应答的细胞内信号受损。这些特征导致UPS和其他蛋白酶的激活，产生肌肉萎缩。肌肉萎缩的另一个潜在发起者是肌肉生长抑制素，它在动物模型和具有某些分解代谢条件的患者的肌肉中表达增加。肌生长抑制素是tgf - β家族的一员；它会抑制肌肉生长，而缺乏它会大大刺激肌肉生长。最近，发现肌肉生长抑制素的药理学抑制可以对抗炎症，增加糖皮质激素和胰岛素/IGF-1信号通路受损，最重要的是，可以防止癌症和肾衰竭啮齿动物模型中的肌肉萎缩。肌生长抑制素拮抗剂作为一种治疗肌肉萎缩症的药物应成为临床研究的课题。
PURPOSE OF REVIEW: To understand the mechanisms of muscle wasting and how inhibiting myostatin signaling affects them.RECENT FINDINGS: Myostatin signaling is critical for the understanding of the pathogenesis of muscle wasting as blocking signaling mitigates muscle losses in rodent models of catabolic diseases including cancer, chronic kidney, or heart failure.SUMMARY: Muscle wasting increases the risks of morbidity and mortality. But, the reliability of estimates of the degree of muscle wasting is controversial as are definitions of terms like cachexia. Much information has been learnt about the pathophysiology of muscle wasting, including the major role of the ubiquitin-proteasome system (UPS) which along with other proteases degrades protein and limits protein synthesis. In contrast, few successful strategies for reversing muscle loss have been tested. Several catabolic conditions are characterized by inflammation, increased glucocorticoid production, and impaired intracellular signaling in response to insulin and IGF-1. These characteristics lead to activation of the UPS and other proteases producing muscle wasting. Another potential initiator of muscle wasting is myostatin and its expression is increased in muscles of animal models and patients with certain catabolic conditions. Myostatin is a member of the TGF-beta family; it suppresses muscle growth and its absence stimulates muscle growth substantially. Recently, pharmacologic suppression of myostatin was found to counteract inflammation, increased glucocorticoids and impaired insulin/IGF-1 signaling and most importantly, prevents muscle wasting in rodent models of cancer and kidney failure. Myostatin antagonism as a therapy for patients with muscle wasting should become a topic of clinical investigation.