mitoAMPK in exercise benefits

mitoAMPK 在运动中的益处

• 批准号: 10408037
• 负责人: Zhen Yan
• 金额: --
• 依托单位: UNIVERSITY OF VIRGINIA
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408037
• 关键词: 5' -AMP-activated protein kinase; Adenine Nucleotides; Adult; Autophagocytosis; Bioenergetics; Biological Models; Biology; CRISPR/Cas technology; Chronic Disease; Color; Complex; Cultured Cells; Data; Deterioration; Development; Diabetes Mellitus; Disease; Dynamin; Electric Stimulation; Ensure; Enzymes; Exercise; Experimental Designs; Experimental Models; Fluorescence; Fluorescence Resonance Energy Transfer; Foundations; Future; Gene Transfer; Health Benefit; Health Promotion; Heart; Holoenzymes; Human; Image; Insulin Resistance; Intervention; Ischemia; Kidney; Knockout Mice; Laboratories; Lead; Link; Maintenance; Mediating; Membrane Potentials; Metabolic; Metabolism; Mitochondria; Motor; Mus; Muscle; Muscle Cells; Muscle Contraction; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Outer Mitochondrial Membrane; Oxidative Phosphorylation; Oxidative Stress; Pharmacology; Phosphorylation; Phosphotransferases; Physical Performance; Power Plants; Prevention; Process; Production; Protein Kinase; Proteins; Quality Control; Reactive Oxygen Species; Regulation; Reporter; Role; Running; Signal Transduction; Signaling Molecule; Skeletal Muscle; Specificity; Stress; Technology; Testing; Tissues; effective intervention; endurance exercise; exercise capacity; exercise training; fight against; frailty; functional adaptation; gain of function; improved; in vivo; inhibitor; innovation; insulin sensitivity; loss of function; novel; physical conditioning; prevent; response; sensor; skeletal; therapeutic development; therapeutically effective; treadmill; two-photon

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.

项目总结/摘要 经常运动可促进体能和健康，并预防各种疾病。这些 这些益处在很大程度上是由骨骼肌中的反应和适应，特别是线粒体重塑介导的。 肌肉. 5'腺苷酸活化蛋白激酶（AMPK）是一种生物能量传感器，对于维持细胞的功能至关重要。 AMPK信号转导与线粒体重塑和功能性 在正常和疾病条件下的适应。然而，AMPK信号传导的确切机制在 亚细胞特异性对线粒体重塑的控制仍不清楚。我们发现了一个 一种新的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）。我们还 获得的初步数据表明，抑制mitoAMPK阻断运动诱导的线粒体自噬，这是运动诱导线粒体自噬的关键步骤， 在骨骼肌线粒体质量控制中。我们现在提出一个全新的假设， mitoAMPK在运动过程中优先在能量应激的线粒体上被激活，介导 功能障碍或受损线粒体的精确线粒体自噬，用于功能和代谢 为了检验这一假设，我们提出： 1)确定在骨骼肌中，mitoAMPK是否优先在能量应激的线粒体中被激活。 2)阐明mitoAMPK在运动诱导的线粒体自噬中的作用。 3)mitoAMPK在运动训练诱导的功能和代谢中的作用 适应 拟议的研究将利用我们对mitoAMPK的新发现， 这一重要信号分子在肌肉生物学和代谢中的调节和功能特征。的 实验设计和模型系统在概念和技术上都是创新的。其成果将 显着提高对运动诱导的线粒体自噬和适应的机制理解，具有很大的 对治疗和预防慢性病的治疗方法的未来发展的潜在影响， 比如2型糖尿病