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.

项目摘要/摘要 定期运动可以促进身体表现和健康，并防止各种类型的疾病。这些 在骨骼中的响应和适应性，尤其是线粒体重塑的基本上介导了好处 肌肉。 5'AMP激活蛋白激酶（AMPK）是一种生物能传感器，对维护至关重要 代谢同源性和AMPK信号传导与线粒体重塑和功能相关 在正常和疾病条件下适应。但是，AMPK信号传导的确切机制 用亚细胞特异性控制线粒体重塑仍然晦涩。我们发现了一个身体 新型AMPK复合物（α1，β2和γ1亚基）与线粒体（称为mitoAmpk）的关联 并在运动和缺血条件下揭示其激活（T172磷酸化）。我们也有 获得了初步数据，以表明抑制MitoAmpk障碍运动引起的线索，这是关键步骤 在线粒体质量控制中，骨骼肌。现在，我们提出了一个完全新颖的假设 在运动过程中，在有效的应力线粒体上，MitoAmpk最好被激活 功能和代谢的线粒体功能失调或损坏的精确线粒体 改编以检验这一假设，我们提出： 1）确定在有效的骨骼肌线粒体有效应力的线粒体时，优选地激活mitoampk。 2）阐明MitoAmpk在运动引起的线索中的作用。 3）MITOAMPK在运动训练引起的功能和代谢中的功能作用 改编。 拟议的研究将利用我们的新型Mitoampk发现，该发现揭示了全新的 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是创新的。调查结果会 显着提高了对运动引起的线粒体和适应的机械理解， 潜在对治疗和预防慢性疾病治疗的未来发展的潜在影响， 像2型糖尿病。