Department of Internal Medicine, University of Washington Medical Center Seattle, WA, USA ; Papé Family Pediatric Research Institute, Oregon Health and Science University Portland, OR, USA.
Department of Internal Medicine, University of Washington Medical Center Seattle, WA, USA.
Front Physiol. 2015 Feb 3;6:12. doi: 10.3389/fphys.2015.00012. eCollection 2015.
Glucocorticoids are highly conserved fundamental regulators of energy homeostasis. In response to stress in the form of perceived danger or acute inflammation, glucocorticoids are released from the adrenal gland, rapidly mobilizing energy from carbohydrate, fat and protein stores. In the case of inflammation, mobilized protein is critical for the rapid synthesis of acute phase reactants and an efficient immune response to infection. While adaptive in response to infection, chronic mobilization can lead to a profound depletion of energy stores. Skeletal muscle represents the major body store of protein, and can become substantially atrophied under conditions of chronic inflammation. Glucocorticoids elicit the atrophy of muscle by increasing the rate of protein degradation by the ubiquitin-proteasome system and autophagy lysosome system. Protein synthesis is also suppressed at the level of translational initiation, preventing the production of new myofibrillar protein. Glucocorticoids also antagonize the action of anabolic regulators such as insulin further exacerbating the loss of protein and muscle mass. The loss of muscle mass in the context of chronic disease is a key feature of cachexia and contributes substantially to morbidity and mortality. A growing body of evidence demonstrates that glucocorticoid signaling is a common mediator of wasting, irrespective of the underlying initiator or disease state. This review will highlight fundamental mechanisms of glucocorticoid signaling and detail the mechanisms of glucocorticoid-induced muscle atrophy. Additionally, the evidence for glucocorticoids as a driver of muscle wasting in numerous disease states will be discussed. Given the burden of wasting diseases and the nodal nature of glucocorticoid signaling, effective anti-glucocorticoid therapy would be a valuable clinical tool. Therefore, the progress and potential pitfalls in the development of glucocorticoid antagonists for muscle wasting will be discussed.
糖皮质激素是能量平衡的高度保守的基本调节剂。在感知到危险或急性炎症的形式的应激下，糖皮质激素从肾上腺释放出来，迅速从碳水化合物、脂肪和蛋白质储存中动员能量。在炎症的情况下，动员的蛋白质对于快速合成急性期反应物和对感染的有效免疫反应至关重要。虽然在感染时是适应性的，但慢性动员会导致能量储存的严重耗竭。骨骼肌是蛋白质的主要身体储存库，在慢性炎症条件下会发生显著萎缩。糖皮质激素通过增加泛素-蛋白酶体系统和自噬溶酶体系统的蛋白质降解率来引起肌肉萎缩。蛋白质合成也在翻译起始水平受到抑制，防止新肌原纤维蛋白的产生。糖皮质激素还拮抗胰岛素等合成代谢调节剂的作用，进一步加剧蛋白质和肌肉质量的丧失。慢性疾病中肌肉质量的丧失是恶病质的一个关键特征，大大增加了发病率和死亡率。越来越多的证据表明，糖皮质激素信号是消耗的共同介导者，无论潜在的启动子或疾病状态如何。这篇综述将重点介绍糖皮质激素信号的基本机制，并详细描述糖皮质激素诱导的肌肉萎缩的机制。此外，还将讨论糖皮质激素作为许多疾病状态下肌肉消耗的驱动因素的证据。鉴于消耗性疾病的负担和糖皮质激素信号的节点性质，有效的抗糖皮质激素治疗将是一种有价值的临床工具。因此，将讨论用于治疗肌肉消耗的糖皮质激素拮抗剂的进展和潜在陷阱。
