The Role of TCTP in the Regulation of Skeletal Muscle Mass

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起着重要作用，然而，调节mTOR信号传导的分子机制仅被模糊地定义。然而，正在取得进展，最近的研究表明，高度保守的免疫控制肿瘤蛋白（TCTP）可以通过充当GTdR 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，TCTP的表达可以通过对mTOR抑制剂雷帕霉素敏感的机制由生长促进刺激快速诱导。基于这些观察，我们设想了TCTP以前馈方式调节mTOR信号传导的机制的可能性，并且这种机制可以解释急性生长刺激（例如，60次高阻力收缩）如何促进mTOR信号传导的高度延长（> 36小时）的激活。为了支持这种可能性，我们发现TCTP表达通过mTOR依赖性机制响应于机械负荷而升高。此外，我们已经确定TCTP的过表达足以诱导肥大。结合这些观察结果，我们得出了我们的中心假设：生长促进刺激通过mTOR依赖性机制诱导TCTP表达，TCTP表达的变化反过来调节mTOR信号传导、蛋白质合成和纤维大小。为了检验这一假设，我们将使用体内生物化学、分子和遗传方法的组合，同时追求以下三个具体目标：1）确定各种生长促进刺激物是否通过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;和3）确定TCTP是否通过需要TCTP对Rheb的GEF活性的mTOR依赖性机制诱导肥大。这些研究的结果预计将坚定地确立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，大大促进我们对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，骨骼肌质量的维持对于运动，疾病预防和生活质量至关重要。因此，该项目与公共卫生有关，因为其结果可能导致确定治疗目标，旨在预防衰老，固定，卧床休息，航天，恶病质，肌肉营养不良和肌病等条件下的骨骼肌萎缩。

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.