Mechanisms underlying myostatin regulation and activity

肌肉生长抑制素调节和活性的机制

• 批准号: 7944957
• 负责人: SE-JIN LEE
• 金额: $ 36.19万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944957
• 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; Fatty acid glycerol esters; 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; member; muscle form; myostatin; public health relevance; 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. 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.

描述（由申请人提供）：肌生长抑制素（MSTN）是一种分泌蛋白，在调节肌肉质量中起重要作用。我们最初在哺乳动物转化生长因子-ss （TGF-ss）超级家族的新成员筛选中发现了肌肉生长抑制素。我们发现Mstn在胚胎发育和成年小鼠的骨骼肌谱系中都有特异性表达，并且在小鼠中靶向删除Mstn基因会导致骨骼肌质量的急剧和广泛增加。随后对牛、羊、狗和人类的基因研究都表明，肌肉生长抑制素作为肌肉质量的负调节因子的功能在物种间高度保守。肌肉生长抑制素通常限制肌肉质量的研究表明，在肌肉退行性疾病、神经肌肉疾病、恶病质和与年龄相关的肌肉减少症等以衰弱性肌肉损失为特征的疾病状态下，靶向肌肉生长抑制素途径可能有助于促进肌肉生长和再生。事实上，许多研究已经证明在许多这些疾病中靶向肌肉生长抑制素途径的有益作用。为了开发利用这一信号通路用于人类治疗的策略和方法，我们的大部分工作都集中在理解肌肉生长抑制素信号传递到靶细胞的机制以及肌肉生长抑制素活性被调节的机制上。该项目的总体目标是继续努力阐明肌肉生长抑制素作用的分子和细胞机制。这个项目的一个主要目标将是确定肌肉中的细胞类型，这些细胞类型是体内肌肉生长抑制素信号传导的直接目标。关于肌肉生长抑制素是通过信号传导给卫星细胞（即肌肉中的干细胞），还是直接传导给肌纤维，目前存在相当大的争议。在这个项目的第一部分，我们将尝试确定卫星细胞在介导肌肉生长抑制素信号传导和肌肉生长抑制素抑制作用中的作用。这些研究不仅对理解骨骼肌生长的基本生物学很重要，而且对基于靶向这一途径的临床应用也很重要，因为一个关键的问题是，基于肌肉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的效果。在该项目的第二部分，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以及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为肌肉生长抑制素及其调控成分的作用机制提供重要的见解，这些发现可能对评估哪种疾病状态可能对靶向该途径的治疗剂最敏感以及确定最有效的治疗干预策略具有重要意义。