Mechanisms underlying myostatin regulation and activity

说明(申请人提供)：肌肉生长抑制素(MSTN)是一种分泌型蛋白质，在调节肌肉质量方面起着重要作用。我们最初在筛选哺乳动物转化生长因子-ss(TGF-ss)超家族的新成员时发现了myostatin。我们发现，MSTN在胚胎发育期间和成年小鼠的骨骼肌谱系中都有特异的表达，并且在小鼠中靶向缺失MSTN基因会导致骨骼肌量的显著和广泛的增加。随后在牛、羊、狗和人类身上进行的遗传学研究都表明，肌肉抑制素作为肌肉质量的负调节因子的功能在不同物种之间高度保守。肌肉抑制素正常作用于限制肌肉质量的证据表明，靶向myostatin途径可能有助于促进肌肉生长和再生，这些疾病的特征是肌肉衰弱，包括肌肉退行性疾病、神经肌肉疾病、恶病质和年龄相关性石棺减少。事实上，许多研究已经证明，在许多这样的疾病环境中，靶向肌肉生长抑素途径的有益效果。为了开发利用这一信号通路用于人类治疗应用的策略和方法，我们将大部分工作集中在了解myostatin信号向靶细胞传递以及myostatin活性受调控的机制上。这个项目的总体目标是继续我们的努力，以阐明肌肉生长抑素作用的分子和细胞机制。该项目的一个主要目标将是确定肌肉中哪些细胞类型是肌肉中肌肉抑制素信号的直接靶点。对于肌肉抑制素通常是通过向卫星细胞(即驻留在肌肉中的干细胞)还是直接向肌纤维发送信号来发挥作用，存在着相当大的争议。在这个项目的第一部分，我们将尝试确定卫星细胞在介导myostatin信号转导中的作用以及myostatin抑制的作用。这些研究不仅对于了解骨骼肌生长的基本生物学，而且对于以这一途径为靶点的临床应用都是重要的，因为一个关键的问题是，在卫星细胞种群已经耗尽的疾病环境中，基于肌肉抑制素的治疗是否会产生有益的效果。在这个项目的第二部分，我们将继续努力了解这一监管体系的关键组成部分的作用。特别是，我们将在小鼠身上使用遗传学方法来进一步表征激活素II型受体在介导肌肉生长抑制素信号转导中的作用，以及卵泡抑素在调节肌肉生长抑素活性中的作用。综上所述，我们相信，这些研究的结果将为肌肉抑制素及其调节成分的作用机制提供重要的见解，这些发现可能对评估哪些疾病状态可能对针对这一途径的治疗药物最敏感，以及确定最有效的治疗干预策略具有重要意义。 与公共健康相关：这项提案的总体目标是研究肌肉抑制素的调节和活性的潜在机制，肌肉抑制素是一种信号分子，在调节骨骼肌生长方面发挥关键作用。这些研究可能对预防和治疗广泛的肌肉萎缩疾病，如肌营养不良症、骨质疏松症和恶病质，以及代谢性疾病，如肥胖症和II型糖尿病具有重要意义。

DESCRIPTION (provided by applicant): Myostatin (MSTN) is a secreted protein that plays an important role in regulating muscle mass. We originally identified myostatin in a screen for new members of the transforming growth factor-ss (TGF-ss) super family in mammals. We showed that Mstn is expressed specifically in the skeletal muscle lineage both during embryonic development and in adult mice and that targeted deletion of the Mstn gene in mice leads to a dramatic and widespread increase in skeletal muscle mass. Subsequent genetic studies in cattle, sheep, dogs, and humans have all shown that the function of myostatin as a negative regulator of muscle mass has been highly conserved across species. The demonstration that myostatin normally acts to limit muscle mass has suggested the possibility that targeting the myostatin pathway may have utility for enhancing muscle growth and regeneration in disease states characterized by debilitating muscle loss, including muscle degenerative diseases, neuromuscular diseases, cachexia, and age-related sarcopenia. Indeed, a number of studies have demonstrated beneficial effects of targeting the myostatin pathway in many of these disease settings. In order to develop strategies and methods for exploiting this signaling pathway for human therapeutic applications, we have focused much of our work on understanding the mechanisms by which myostatin signals to target cells and by which myostatin activity is regulated. The overall goal of this project is to continue our efforts to elucidate the molecular and cellular mechanisms underlying myostatin action. A major goal of this project will be to identify the cell types in muscle that are the direct targets for myostatin signaling in vivo. There is considerable debate as to whether myostatin normally exerts its effect by signaling to satellite cells, which are the stem cells resident in muscle, or directly to myofibers. In the first part of this project, we will attempt to determine the role of satellite cells in mediating myostatin signaling and the effects of myostatin inhibition. These studies will be important not only for understanding the basic biology of skeletal muscle growth but also for pursuing clinical applications based on targeting this pathway, as a critical question has been whether therapies based on myostatin inhibition will have beneficial effects in disease settings where the satellite cell population has already been depleted. In the second part of this project, we will continue our efforts to understand the roles of key components of this regulatory system. In particular, we will use genetic approaches in mice to characterize further the role of activin type II receptors in mediating myostatin signaling and the role of follistatin in regulating myostatin activity. Taken together, we believe that the results of these studies will provide important insights into the mechanism of action of myostatin and its regulatory components and that these findings could have important implications both for assessing which disease states might be most responsive to therapeutic agents targeting this pathway and for identifying the most effective strategies for therapeutic intervention. PUBLIC HEALTH RELEVANCE: The overall aim of this proposal is to investigate the mechanisms underlying the regulation and activity of myostatin, which is a signaling molecule that plays a critical role in regulating skeletal muscle growth. These studies could have important implications for the prevention and treatment of a wide range of muscle wasting diseases, like muscular dystrophy, sarcopenia, and cachexia, as well as metabolic diseases, like obesity and type II diabetes.