mitoAMPK in exercise benefits

mitoAMPK 在运动中的益处

• 批准号: 10765945
• 负责人: Zhen Yan
• 金额: $ 43.06万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10765945
• 关键词: mitoAMPK; exercise; benefits

PROJECT SUMMARY/ABSTRACT Regular exercise promotes physical performance and health, and prevent various types of diseases. These benefits are largely mediated by responses and adaptations, particularly mitochondrial remodeling, in skeletal muscle. 5' AMP-activated protein kinase (AMPK) is a bioenergetics sensor that is critical for the maintenance of metabolic homoeostasis, and AMPK signaling has been linked to mitochondrial remodeling and functional adaptations under normal and disease conditions. However, the precise mechanism of AMPK signaling in control of mitochondrial remodeling with subcellular specificity remains obscure. We discovered a physical association of a novel AMPK complex (α1, β2 and γ1 subunits) with mitochondria (referred to as mitoAMPK) in and unveiled its activation (T172 phosphorylation) under exercise and ischemic conditions. We have also obtained preliminary data to show that inhibition of mitoAMPK blocks exercise-induced mitophagy, a key step in mitochondrial quality control, in skeletal muscle. We now propose a completely novel hypothesis that mitoAMPK is preferentially activated at energetically stressed mitochondria during exercise, mediating precision mitophagy of dysfunctional or damaged mitochondria for functional and metabolic adaptations To test this hypothesis, we propose: 1) Determine if mitoAMPK is preferentially activated at energetically stressed mitochondria in skeletal muscle. 2) Elucidate the role of mitoAMPK in exercise-induced mitophagy. 3) Eetermine the functional role of mitoAMPK in exercise training-induced functional and metabolic adaptations. The proposed studies will capitalize on our novel findings of mitoAMPK that reveals completely new regulatory and functional features of this important signaling molecule in muscle biology and metabolism. The experimental design and model systems are both conceptually and technically innovative. The findings will significantly improve the mechanistic understanding of exercise-induced mitophagy and adaptations, with great potential impact on the future development of therapeutics for treatment and prevention ofchronic diseases, like type 2 diabetes.

项目概要/摘要 定期锻炼可以促进身体机能和健康，并预防各种疾病。 益处很大程度上是由骨骼中的反应和适应介导的，特别是线粒体重塑 5' AMP 激活蛋白激酶 (AMPK) 是一种生物能传感器，对于维持肌肉至关重要。 AMPK 信号传导与线粒体重塑和功能相关 然而，AMPK 信号传导的精确机制在正常和疾病条件下都存在。 我们发现了亚细胞特异性对线粒体重塑的控制仍然不清楚。 新型 AMPK 复合物（α1、β2 和 γ1 亚基）与线粒体（称为 mitoAMPK）的关联 并揭示了其在运动和缺血条件下的激活（T172 磷酸化）。 获得初步数据表明，抑制 mitoAMPK 可以阻断运动诱导的线粒体自噬，这是一个关键步骤 在线粒体质量控制和骨骼肌中，我们现在提出了一个全新的假设： mitoAMPK 在运动过程中优先在受到能量压力的线粒体处被激活，介导 功能失调或受损线粒体的精确线粒体自噬，以实现功能和代谢 为了检验这个假设，我们建议： 1) 确定 mitoAMPK 是否优先在骨骼肌中受到能量应激的线粒体处被激活。 2）阐明mitoAMPK在运动诱导的线粒体自噬中的作用。 3) 确定mitoAMPK在运动训练诱发的功能和代谢中的功能作用 适应。 拟议的研究将利用我们的 mitoAMPK 的新发现，揭示全新的 这种重要信号分子在肌肉生物学和代谢中的调节和功能特征。 实验设计和模型系统在概念和技术上都具有创新性。 显着提高了对运动诱导的线粒体自噬和适应机制的理解，具有很大的作用 对治疗和预防慢性病的疗法的未来发展的潜在影响， 比如2型糖尿病。