The regulation of protein translation in skeletal muscle by androgens

描述（由申请人提供）：我在追求这个职业发展奖，以促进转化研究的职业生涯，重点是阐明机制和发展战略，以减轻骨骼肌萎缩。与年龄和疾病相关的肌肉质量损失与巨大的社会和经济成本有关，表现为力量受损、功能受限、身体残疾和丧失独立性。令人遗憾的是，缺乏对抗肌肉萎缩的疗法，并且对现有疗法发挥其作用的手段仍然知之甚少。该职业发展奖的主要目的是研究一种合理的机制，通过该机制，原型雄激素睾酮可以协调调节骨骼肌中的合成代谢和分解代谢过程;即，通过调节磷脂酰肌醇3-激酶（PI 3-激酶）/Akt信号通路。这将在一个跨学科团队的帮助下进行，该团队由具有雄激素生物学专业知识的赞助商和对Akt和蛋白质翻译科学做出重大贡献的共同赞助商组成。首先，在基于细胞的模型中，我将描述睾酮对PI 3-激酶、Akt和调节蛋白质翻译的关键效应激酶的调节。接下来，将在一种新的条件性肌肉特异性Akt 1过表达转基因小鼠中分析睾酮对这些分子靶点、肌肉质量和肌肉功能的影响。最后，雄激素作用的分子基础将在人类中使用肌肉活检进行研究，该肌肉活检是在一项正在进行的研究中获得的，该研究是在睾酮水平较低和活动受限的老年男性中进行的。除了赞助商和共同赞助商的支持外，波士顿医疗中心的环境提供了丰富的智力和技术资源，以确保本提案的成功以及我作为独立研究者的发展。相关性：与年龄相关的肌肉质量损失与巨大的社会和经济成本有关。随着我们老年人口的持续增长，探索合成代谢疗法（如睾酮）促进肌肉生长的潜在机制是有价值的。这项工作可能有助于开发新的，更安全，更有效的肌肉萎缩疗法。

DESCRIPTION (provided by applicant): I am in pursuit of this career development award to foster a translational research career focused on elucidating the mechanisms and developing strategies to attenuate skeletal muscle wasting. The age- and disease-related loss in muscle mass is associated with substantial social and economic costs and evidenced by impairments in strength, limitations in function, physical disability and loss of independence. Regrettably, there is a paucity of therapies to combat muscle wasting and the means by which existing therapeutics exert their effects remain poorly understood. The primary objective of this career development award is to investigate a plausible mechanism by which the prototypical androgen, testosterone, may coordinately regulate anabolic and catabolic processes in skeletal muscle; namely, through regulation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathway. This will be pursued with the help of an interdisciplinary team consisting of a sponsor with expertise in the biology of androgens, and co-sponsors who have made significant contributions to the science of Akt and protein translation. First, in cell-based models, I will characterize the regulation of PI3-kinase, Akt and key effector kinases that modulate protein translation, by testosterone. Next, the effects of testosterone on these molecular targets, muscle mass and muscle function will be analyzed in a novel conditional, muscle-specific Akt1 overexpressing transgenic mouse. Lastly, the molecular basis for androgen action will be investigated in humans using muscle biopsies acquired in an ongoing study of testosterone administration in older men with low testosterone levels and mobility limitations. In addition to the support of sponsors and co-sponsors, the environment at Boston Medical Center provides rich intellectual and technical resources to ensure the success of this proposal and my development as an independent investigator. Relevance: The age-related loss in muscle mass is associated with substantial social and economic costs. With the continued growth of our aged population, there is merit in exploring the underlying mechanisms by which anabolic therapies, such as testosterone, promote muscle growth. Potentially, this work will contribute to the development of novel, safer and more effective therapies for muscle wasting.