Protein arginine methyltransferase biology in skeletal muscle

本研究计划旨在继续我们正在进行的研究蛋白精氨酸甲基转移酶（PRMTs）在确定、维持和重塑骨骼肌生物学中的作用的工作。PRMTs是一个由九种酶组成的酶家族，它们催化靶蛋白上精氨酸残基的甲基化，从而介导多种细胞内功能，这些功能对生存至关重要。我们和其他人的观察清楚地表明，PRMTs正在成为骨骼肌表型和可塑性的重要介质。体育活动的增加或减少以及饮食的改变（如禁食）会引起骨骼肌生物学的显著变化。众所周知，包括人类在内的许多动物物种都有这种适应性。这是如何发生的还不完全清楚。本提案的目的是调查我们认为在理解骨骼肌PRMT生物学方面目前尚未解决的最重要的前沿研究问题。我们将利用有针对性的策略来研究PRMTs下游基因表达途径中的许多步骤，以及广泛地使用无偏倚的转录组学和蛋白质组学方法来研究肌肉对急性或慢性肌肉可塑性的反应。这将使用细胞生物学、生物化学和分子方法在培养的肌肉细胞、体内动物模型和人类参与者中进行。我们的研究项目的结果将对我们如何看待PRMTs在肌肉细胞背景下的重要性产生重大影响，并将允许我们修改我们对这些酶对骨骼肌结构和功能的细胞和生理影响的思考。

This research proposal is designed to continue our ongoing work in investigating the roles of protein arginine methyltransferases (PRMTs) in determining, maintaining, and remodelling skeletal muscle biology. PRMTs are a family of nine enzymes that catalyze the methylation of arginine residues on target proteins, thereby mediating a diverse set of intracellular functions that are indispensable for survival. Observations made by us and others clearly demonstrate that PRMTs are emerging as important mediators of skeletal muscle phenotype and plasticity. Increases or decreases in physical activity, and dietary alterations such as fasting, elicit significant alterations in skeletal muscle biology. These adaptations are known to occur across a wide range of animal species, including humans. How this takes place is not fully understood. The purpose of this proposal is to investigate what we feel are the most important, cutting-edge research questions that are currently unresolved in understanding PRMT biology in skeletal muscle. We will investigate this by utilizing targeted strategies aimed at examining many steps in the gene expression pathway downstream of PRMTs, as well as broadly by using unbiased transcriptomic and proteomic approaches in muscle responding to acute or chronic cues for muscle plasticity. This will be performed using cell biology, biochemical and molecular approaches in muscle cells in culture, in vivo animal models, and in human participants. The results of our research program will have a significant impact on how we view the importance of PRMTs within the context of the muscle cell, and will allow us to revise our thinking about the cellular and physiological impacts of these enzymes on skeletal muscle structure and function.