Mechanisms Underlying Myostatin Regulation and Activity

肌肉生长抑制素调节和活性的潜在机制

• 批准号: 8690763
• 负责人: SE-JIN LEE
• 金额: $ 33.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-19 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690763
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Aging; Amyotrophic Lateral Sclerosis; Biology; Cachexia; Canis familiaris; Cattle; Cells; Chronic Obstructive Airway Disease; Degenerative Disorder; Disease; Embryonic Development; Family; Follistatin; Genes; Genetic; Goals; Growth; Human; Hyperplasia; Hypertrophy; Malignant Neoplasms; Mammals; Mediating; Metabolic Diseases; Methods; Modeling; Molecular; Mus; Muscle; Muscle Fibers; Muscular Dystrophies; Myopathy; Natural regeneration; Neuromuscular Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Play; Population; Prevention; Proteins; Regulation; Role; Sepsis; Sheep; Signal Pathway; Signal Transduction; Signaling Molecule; Skeletal Muscle; Spinal Muscular Atrophy; Stem cells; Steroids; System; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transforming Growth Factors; Type II Activin Receptors; Wasting Syndrome; Work; age related; base; cell type; cellular targeting; clinical application; glucose metabolism; in vivo; insight; lipid metabolism; member; muscle form; myostatin; receptor function; sarcopenia; satellite cell; skeletal muscle growth

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.

描述（申请人提供）：肌生长抑制素（Myostatin）是一种分泌性蛋白，在调节肌肉质量中发挥重要作用。我们最初在筛选哺乳动物中转化生长因子-β（TGF-β）超家族的新成员时发现了肌生长抑制素。我们发现，Mcl 2在胚胎发育和成年小鼠的骨骼肌谱系中特异性表达，并且小鼠Mcl 2基因的靶向缺失导致骨骼肌质量的显著和广泛增加。随后对牛、羊、狗和人类的遗传研究都表明，肌生长抑制素作为肌肉质量负调节因子的功能在物种间高度保守。肌生长抑制素通常用于限制肌肉质量的证明表明，靶向肌生长抑制素途径可能具有在以使人衰弱的肌肉损失为特征的疾病状态（包括肌肉变性疾病、神经肌肉疾病、恶病质和年龄相关的肌肉减少症）中增强肌肉生长和再生的效用。事实上，许多研究已经证明了在许多这些疾病环境中靶向肌肉生长抑制素途径的有益效果。为了开发利用该信号通路用于人类治疗应用的策略和方法，我们的大部分工作集中在了解肌生长抑制素向靶细胞发出信号以及调节肌生长抑制素活性的机制上。这个项目的总体目标是继续我们的努力，阐明肌肉生长抑制素作用的分子和细胞机制。该项目的一个主要目标是确定肌肉中的细胞类型，这些细胞是体内肌肉生长抑制素信号传导的直接靶点。关于肌生长抑制素是否通过向卫星细胞（肌肉中的干细胞）或直接向肌纤维发出信号来发挥作用，存在相当大的争议。在这个项目的第一部分，我们将试图确定卫星细胞在介导肌肉生长抑制素信号传导和肌肉生长抑制素抑制的影响中的作用。这些研究不仅对于理解骨骼肌生长的基础生物学非常重要，而且对于基于靶向该途径的临床应用也很重要，因为一个关键问题是基于肌生长抑制素抑制的疗法是否会在卫星细胞群已经耗尽的疾病环境中产生有益效果。在本项目的第二部分，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，我们将在小鼠中使用遗传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传导中的作用和卵泡抑素在调节肌肉生长抑制素活性中的作用。综上所述，我们相信这些研究的结果将提供重要的见解肌肉生长抑制素及其调控成分的作用机制，这些发现可能具有重要的意义，既评估哪些疾病状态可能是最敏感的治疗药物靶向这一途径，并确定最有效的治疗干预策略。