The Role of TCTP in the Regulation of Skeletal Muscle Mass

TCTP 在骨骼肌质量调节中的作用

• 批准号: 8443132
• 负责人: Craig Andrew Goodman
• 金额: $ 20.32万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443132
• 关键词: 5' Untranslated Regions; Acute; Aging; Atrophic; Attenuated; Bed rest; Biochemical; Cachexia; Clenbuterol; Data; Dexamethasone; Fiber; Genetic Translation; Goals; Growth; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Hypertrophy; Immobilization; Lead; Maintenance; Mechanics; Messenger RNA; Metabolism; Molecular; Molecular Genetics; Movement; Mus; Muscular Atrophy; Muscular Dystrophies; Myopathy; Oligonucleotides; Outcome; Play; Protein Biosynthesis; Protein Kinase; Proteins; Public Health; Pyrimidines; Quality of life; Regulation; Resistance; Role; Signal Transduction; Signaling Protein; Sirolimus; Skeletal Muscle; Space Flight; Stimulus; Structure; Testing; Transgenic Mice; base; cell type; disorder prevention; feeding; genetic regulatory protein; high risk; in vivo; inhibitor/antagonist; insight; mTOR protein; muscle form; mutant; novel; overexpression; p23 translationally controlled tumor protein; prevent; protein expression; response; translation factor

DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) plays a fundamental role in the regulation of skeletal muscle mass, however, the molecular mechanism(s) that regulate mTOR signaling have only been vaguely defined. Nevertheless, advances are being made, and recent studies suggest that the highly conserved translationally- controlled tumor protein (TCTP) can regulate mTOR signaling by acting as a guanine exchange factor (GEF) for the GTPase Rheb. Furthermore, previous studies have shown that the expression of TCTP can be rapidly induced by growth promoting stimuli through a mechanism that is sensitive to the mTOR inhibitor, rapamycin. Based on these observations, we have envisioned the potential for a mechanism in which TCTP regulates mTOR signaling in a feed-forward manner, and such a mechanism might explain how an acute growth stimulus (e.g. 60 high-resistance contractions) can promote a highly prolonged (>36hr) activation of mTOR signaling. In support of this possibility, we have found that TCTP expression is elevated in response to mechanical loading via an mTOR-dependent mechanism. Furthermore, we have determined that overexpression of TCTP is sufficient to induce hypertrophy. Combined, these observations have led us to our central hypothesis: growth promoting stimuli induce TCTP expression via an mTOR-dependent mechanism, and changes in TCTP expression, in-turn, regulate mTOR signaling, protein synthesis and fiber size. To test this hypothesis we will use a combination of in vivo biochemical, molecular and genetic approaches while pursuing the following three specific aims: 1) Determine if various growth promoting stimuli induce TCTP expression via an mTOR- dependent mechanism; 2) Determine if the expression of TCTP regulates protein synthesis and fiber size; and 3) Determine if TCTP induces hypertrophy through an mTOR-dependent mechanism that requires TCTP's GEF activity towards Rheb. The results of these studies are expected to firmly establish TCTP as novel regulator of skeletal muscle mass and they will provide insight into how TCTP exerts this effect. Furthermore, if the central hypothesis is correct, the outcomes will expose a mechanism that substantially advances our understanding of how mTOR signaling and skeletal muscle mass are regulated. PUBLIC HEALTH RELEVANCE: Skeletal muscle is crucial for movement and whole body metabolism, and consequently, the maintenance of skeletal muscle mass is essential for mobility, disease prevention and quality of life. Hence, this project is relevant to public health because the outcomes could lead to the identification of targets for therapies that are aimed at preventing skeletal muscle atrophy during conditions such as aging, immobilization, bedrest, spaceflight, cachexia, muscular dystrophies and myopathies.

描述（由申请人提供）：哺乳动物雷帕霉素靶标（mTOR）在骨骼肌质量的调节中发挥着重要作用，然而，调节mTOR信号传导的分子机制仅被模糊地定义。尽管如此，研究仍在取得进展，最近的研究表明，高度保守的翻译控制肿瘤蛋白 (TCTP) 可以通过充当 GTPase Rheb 的鸟嘌呤交换因子 (GEF) 来调节 mTOR 信号传导。此外，先前的研究表明，促生长刺激可以通过对 mTOR 抑制剂雷帕霉素敏感的机制快速诱导 TCTP 的表达。基于这些观察，我们设想了一种机制，其中 TCTP 以前馈方式调节 mTOR 信号传导，这种机制可能解释急性生长刺激（例如 60 次高阻收缩）如何促进 mTOR 信号传导的高度长时间（>36 小时）激活。为了支持这种可能性，我们发现 TCTP 表达通过 mTOR 依赖性机制响应机械负荷而升高。此外，我们已经确定TCTP的过度表达足以诱导肥大。综合起来，这些观察结果使我们得出了中心假设：生长促进刺激通过 mTOR 依赖性机制诱导 TCTP 表达，而 TCTP 表达的变化反过来又调节 mTOR 信号传导、蛋白质合成和纤维大小。为了检验这一假设，我们将结合使用体内生化、分子和遗传学方法，同时追求以下三个具体目标：1）确定各种生长促进刺激是否通过 mTOR 依赖性机制诱导 TCTP 表达； 2) 确定TCTP的表达是否调节蛋白质合成和纤维尺寸； 3) 确定 TCTP 是否通过 mTOR 依赖性机制诱导肥大，该机制需要 TCTP 对 Rheb 的 GEF 活性。这些研究的结果预计将牢固确立 TCTP 作为骨骼肌质量的新型调节剂，并将深入了解 TCTP 如何发挥这种作用。此外，如果中心假设是正确的，结果将揭示一种机制，极大地增进我们对 mTOR 信号传导和骨骼肌质量如何调节的理解。 公共卫生相关性：骨骼肌对于运动和全身代谢至关重要，因此，维持骨骼肌质量对于活动能力、疾病预防和生活质量至关重要。因此，该项目与公共卫生相关，因为其结果可能导致确定治疗靶点，旨在预防衰老、行动不便、卧床休息、太空飞行、恶病质、肌肉营养不良和肌病等情况下的骨骼肌萎缩。