Investigating Isthmin as an adipose-to-muscle messenger that promotes muscle protein synthesis

摘要 代谢应激源和病理条件，如糖尿病，可导致明显的生理变化 蛋白质调节，导致肌肉萎缩，这是高度相关的发病率。但 这种关联的机制仍然难以捉摸。了解维持肌肉的机制 蛋白质含量对改善胰岛素抵抗和整体代谢健康至关重要。脂肪组织是 通过分泌蛋白质对急性和慢性能量挑战性条件作出反应的内分泌器官， 称为脂肪因子。有证据表明，脂肪因子介导的信号传导在器官发育中起着至关重要的作用。 串扰和系统能量代谢。由于它们的直接信号作用，它们可以被开发为 用于代谢疾病的治疗剂。虽然已经做出了相当大的努力来靶向脂肪组织 作为胰岛素抵抗的一个组成部分，脂肪因子在肌肉生理学中的作用还没有得到充分的研究。我 研究培训计划将利用内分泌学、肌肉生物学、生物信息学和新产生的遗传学。 小鼠模型作为一个工具包，以研究以前研究不足的激素在 促进肌肉生长，副作用可能更少。这一提议检验了中心假设， Isthmin-1（Ism 1）介导脂肪-肌肉串扰，调节肌肉蛋白质稳态。以下目标是 目的1：确定Ism 1是否通过脂肪-肌肉串扰介导肌肉生长。目的 2：确定Ism 1是否改变肌肉蛋白质合成和降解之间的平衡。目标3：使用 磷酸蛋白质组学，以发现调节肌肉蛋白质稳态的新途径。如果成功，这项研究 将在肌肉生长中建立一种新的脂肪-肌肉途径，具有潜在的未来治疗意义， 由于Ism 1激素本身可用作萎缩和 而这种锻炼不是一种选择。 该项目还将为赵博士作为独立研究者的长期目标提供培训， 剖析代谢器官之间的激素串扰，以改善代谢疾病。候选人博士。 Zhao在代谢生理学方面有广泛和合适的培训，有13篇出版物，其中5篇是第一篇。 作者自2016年以来职业发展计划是为使赵博士获得新的实验技能而量身定制的 和肌肉生物学、生物化学和内分泌信号的概念， 内分泌学家和生物化学家。斯坦福大学的环境无与伦比 合作和创新研究以及职业发展培训。综上所述， 我们的工作环境和培训计划将为赵博士的独立职业生涯做好充分准备。的 拟议的研究承诺提供脂肪肌肉串扰的机制见解，以确定治疗 靶点可以对抗肌肉蛋白质损失和相关的代谢疾病。

ABSTRACT Metabolic stressors and pathologic conditions such as diabetes can lead to pronounced physiologic alterations in protein regulation, resulting in muscle atrophy, which is highly associated with morbidity. However, the mechanisms underlying this association remain elusive. Understanding the mechanisms of maintaining muscle protein content is crucial to improving insulin resistance and overall metabolic health. Adipose tissue is an endocrine organ that responds to acute and chronic energetically challenging conditions by secreting proteins, referred to as adipokines. Evidence suggests that signaling mediated by adipokines plays a crucial role in organ crosstalk and systemic energy metabolism. Because of their direct signaling action, they can be developed as therapeutic agents for metabolic diseases. While considerable effort has been made to target the adipose tissue as a component of insulin resistance, the involvement of adipokines in muscle physiology is understudied. My research training plan will leverage endocrinology, muscle biology, bioinformatics, and newly generated genetic mouse models as a toolkit to investigate the function and mechanisms of a previously understudied hormone in promoting muscle growth with potentially fewer side effects. This proposal tests the central hypothesis that Isthmin-1 (Ism1) mediates adipose-muscle crosstalk that regulates muscle proteostasis. The following aims are proposed: Aim 1: To determine whether Ism1 mediates muscle growth through adipose-muscle crosstalk. Aim 2: To determine whether Ism1 alters balance between muscle protein synthesis and degradation. Aim 3: Using phosphoproteomics to discover novel pathways that regulate muscle proteostasis. If successful, this research will establish a novel adipose-muscle pathway in muscle growth with potential future therapeutic implications, since the Ism1 hormone itself can be used as a direct pharmacologic treatment for atrophy and disorders for which exercise is not an option. This project will also provide training for Dr. Zhao’s long-term goal as an independent investigator to dissect the hormonal crosstalk between metabolic organs to improve metabolic diseases. The candidate Dr. Zhao has extensive and suitable prior training in metabolic physiology, with 13 publications including 5 as first- author since 2016. The Career Development Plan is tailored to enable Dr. Zhao to gain new experimental skills and concepts in muscle biology, biochemistry, and endocrine signaling from expert physiologists, endocrinologists, and biochemists in the mentoring team. The environment at Stanford University is unparalleled for collaborative and innovative research and career development training. In summary, the strong mentoring environment and training plan are anticipated to fully prepare Dr. Zhao to launch her independent career. The proposed studies promise to offer mechanistic insights into adipose-muscle crosstalk to identify therapeutic targets that can counter muscle protein loss and associated metabolic disease.