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Exercise-Induced Mitochondrial Biogenesis

运动诱导的线粒体生物发生

基本信息

批准号：
7256359
负责人：
Zhen Yan
金额：
$ 22.49万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7256359
关键词：
Activating Transcription Factor 2 Address Adult Adverse effects Applications Grants Biogenesis Bioluminescence Blood capillaries Chronic Disease Coronary heart disease Disease Dominant-Negative Mutation Elements Exercise Fiber Figs - dietary Fostering Gene Expression Gene Expression Regulation Gene Transfer Genes Genetic Genetic Transcription Image Image Analysis Life MAP2K6 gene MAPK14 gene MM form creatine kinase Measures Mediating Mitochondria Modeling Molecular Mus Muscle Muscle Cells Muscle function Myopathy Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phenotype Physiologic pulse Physiological Play Property Protein Overexpression Pulse taking Regulation Regulator Genes Research Research Personnel Role Running Signal Pathway Signal Transduction Site-Directed Mutagenesis Skeletal Muscle Skeletal system System Testing Time Training Transcriptional Activation Transgenic Mice Up-Regulation base cancer type capillary density gain of function genetic regulatory protein human MAPK14 protein improved in vivo in vivo Model innovation mRNA Expression myocyte-specific enhancer-binding factor 2 neuromuscular activity novel novel therapeutics prevent programs promoter response transcription factor

项目摘要

Skeletal muscles are capable of adaptation in response to endurance training, by changing its fiber type composition, mitochondrial content and capillary densities, hence the functional properties. Orchestrated signal transduction from neuromuscular activity to gene regulatory machinery is responsible for the adaptive changes in the skeletal muscle. We have obtained preliminary results suggesting the importance of the p38 MARK pathway in endurance exercise-induced expression of peroxisome proliferator-activated receptor y co-activator-1a (PGC-1alpha) via myocyte enhancer factor 2 (MEF2) and activating transcription factor 2 (ATF2). Taken together with previous findings in the role PGC-1a in control of mitochondrial biogenesis and fiber specialization, we hypothesize that endurance exercise mediated-activation of p38 MAPK pathway induces transcriptional up-regulation of the PGC-1alpha gene and skeletal muscle adaptation. Our long-term objective is to define the signaling and molecular mechanisms for skeletal muscle adaptation in response to endurance exercise. The specific aims of this grant proposal are to: 1. Determine whether activation of the p38 MAPK pathway is obligatory to contractile activity-induced skeletal muscle adaptation. 2. Ascertain whether overexpression of a dominant negative form of p38p in skeletal muscle negates contractile activity-induced mitochondrial biogenesis and llb-to-lla fiber type switching. 3. Determine whether activation of the p38 MAPK pathway is sufficient to induce skeletal muscle mitochondrial biogenesis and fast-to-slow fiber type switching in transgenic mice. 4. Define the sequence elements and transcription factor-promoter interactions that are required for contractile activity-induced PGC-1a promoter activity in intact skeletal muscle of living mice using real-time bioluminescence imaging analysis. We plan to use both gain-of-function and loss-of-funtion genetic approaches in well-established endurance exercise model in vivo to investigate the regulation of the PGC-1a gene and the importance of the p38 pathway in exercise-induced skeletal muscle adaptation. Since many chronic diseases, such as coronary heart diseases, obesity, type 2 diabetes, and certain types of cancer, are attributable to physical inactivity and skeletal muscle disorders, and since regular exercise has significant positive effects on all of these diseases with no or little side effects, understanding the cellular and molecular mechanism of skeletal muscle adaptation will not only provide information to guide the correct and efficient use of regular exercise training for preventing and treating the diseases, but also facilitate discovery of new therapeutic drugs to combat the diseases

骨骼肌能够通过改变其纤维类型组成、线粒体含量和毛细血管密度来适应耐力训练，从而改变其功能特性。骨骼肌的适应性变化是由神经肌肉活动到基因调控机制的信号转导介导的。我们已经获得了初步的结果表明，在耐力运动诱导的过氧化物酶体增殖物激活受体γ共激活因子-1a（PGC-1 α）的表达，通过肌细胞增强因子2（MEF 2）和激活转录因子2（ATF 2）的p38 MARK途径的重要性。结合先前关于PGC-1a在控制线粒体生物发生和纤维特化中的作用的研究结果，我们假设耐力运动介导了 p38 MAPK通路诱导PGC-1 α基因转录上调和骨骼肌适应我们的长期目标是确定骨骼肌适应耐力运动的信号和分子机制。这项赠款建议的具体目标是： 1.确定p38 MAPK通路的激活是否是收缩活动诱导的骨骼肌适应所必需的。 2.确定骨骼肌中p38 p显性负性形式的过度表达是否否定了收缩活性诱导的线粒体生物发生和llb-到-lla纤维类型转换。 3.确定p38 MAPK通路的激活是否足以诱导转基因小鼠骨骼肌线粒体生物发生和快-慢纤维类型转换。 4.使用实时生物发光成像分析，定义在活小鼠完整骨骼肌中收缩活性诱导的PGC-1a启动子活性所需的序列元件和转录因子-启动子相互作用。我们计划在已建立的体内耐力运动模型中使用功能获得和功能丧失遗传学方法来研究PGC-1a基因的调控以及p38通路在运动诱导的骨骼肌适应中的重要性。由于许多慢性疾病，如冠心病、肥胖症、2型糖尿病和某些类型的癌症，都可归因于缺乏身体活动和骨骼肌疾病，有规律的运动对这些疾病都有显著的积极作用，并且没有或很少有副作用，了解骨骼肌适应的细胞和分子机制不仅可以指导正确和有效地使用有规律的运动训练来预防和治疗这些疾病，而且可以促进新的治疗药物的发现。