Investigating the effects of aerobic and resistance training in vivo on skeletal muscle metabolism in vitro in primary human muscle cells (MoTrMyo)

研究体内有氧和阻力训练对原代人类肌肉细胞体外骨骼肌代谢的影响 (MoTrMyo)

• 批准号: 10227035
• 负责人: Joseph A Houmard
• 金额: $ 67.48万
• 依托单位: ADVENTHEALTH ORLANDO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10227035
• 关键词: Activities of Daily Living; Adipose tissue; Aerobic; Aerobic Exercise; Affect; Biopsy; Blood; Carbohydrates; Cell Culture Techniques; Cell model; Cells; Characteristics; Consumption; Control Groups; DNA Integration; DNA Methylation; Data; Daughter; Epigenetic Process; Exercise; Fatty Acids; Fiber; Funding; Future; Genes; Genetic Transcription; Glycogen; Goals; Health; Health Benefit; Health Status; Human; In Vitro; Individual; Insulin; Intervention; Investigation; Knowledge; Life; Link; Memory; Metabolic; Metabolic Diseases; Mission; Mitochondria; Modality; Modification; Molecular; Morbidity - disease rate; Muscle; Muscle Cells; Muscle Contraction; Muscle Fibers; Muscle Mitochondria; Muscle satellite cell; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Parents; Pathway interactions; Pattern; Physical activity; Population; Proliferating; Property; Research Design; Risk; Risk Factors; Sampling; Signal Transduction; Skeletal Muscle; Testing; Tissue Banks; Tissues; Training; Transducers; United States National Institutes of Health; Work; cell repository; epigenetic regulation; exercise capacity; exercise prescription; exercise training; experimental study; genetic manipulation; imprint; improved; in vitro Model; in vivo; insight; insulin sensitivity; insulin signaling; lifestyle intervention; mortality; novel; oxidation; parent project; repository; resistance exercise; response; satellite cell; self-renewal; skeletal muscle metabolism; skeletal muscle plasticity; stem cells; strength training; trial design

Project Summary/Abstract Low exercise capacity is an important risk factor for all-cause morbidity and mortality. Skeletal muscle is a critical component of exercise capacity through its ability to generate ATP via mitochondrial substrate oxidation (i.e. mitochondrial function). Skeletal muscle properties also influence whole-body insulin sensitivity which affects risk for metabolic diseases (e.g. type 2 diabetes, obesity). Nascent myogenic progenitor cells are a critical component of skeletal muscle plasticity in response to exercise as they proliferate, self‐renew and pass on epigenetic modifications to daughter populations. Meager evidence suggests that these progenitor cells are “imprinted” by lifestyle interventions which confers subsequent metabolic adaptations. The proposed studies will fill a gap in our knowledge and directly assess the ability of exercise training to imprint myogenic progenitor cells in a manner leading to improved exercise capacity and reduced risk for metabolic disease. The primary goal of the present proposal is to leverage the MoTrPAC parent project and determine the distinct abilities of short-term (three months) and life-long (athletes) aerobic training (AT) and resistance training (RT) to imprint key myocellular metabolic properties (insulin sensitivity, mitochondrial function) through epigenetic regulation (DNA methylation, RNA expression) of novel exercise response genes in skeletal muscle progenitor cells. Our secondary goal is to establish a human primary skeletal muscle cell (HSkMC) culture repository from MoTrPAC which can be utilized for future mechanistic interrogations. We hypothesize that exercise training will imprint metabolic properties in skeletal muscle progenitor cells through epigenetic regulation of novel exercise response genes that will differ between AT and RT. We will establish HSkMC cultures from muscle biopsies of 325 individuals (AT, RT, control groups) before and following three months of intervention and 75 athletes (AT and RT) and assess insulin action (insulin-stimulated glycogen synthesis, insulin signal transduction), mitochondrial function (O2 consumption using carbohydrate and fatty acid substrates), DNA methylation and RNA expressions (RNAseq) with associated pathway enrichment analyses. The stated purpose of Aim 1 is to determine the distinct abilities of short-term and life-long AT and RT to imprint key myocellular metabolic properties (insulin sensitivity, mitochondrial function) through epigenetic regulation of exercise response genes. Integration of DNA methylation and RNAseq data will identify novel exercise response genes for subsequent genetic manipulation in vitro to determine its effects on the stated metabolic endpoints. The stated purpose of Aim 2 is to create an HSkMC repository for future investigations. Findings from the proposed studies will provide unprecedented mechanistic insight into the ability of exercise training to confer a “metabolic memory” through epigenetic modification of specific exercise response genes and inform subsequent exercise prescriptions relative to optimizing health benefits gained from exercise.

项目摘要/摘要 低运动能力是全因发病率和死亡率的重要危险因素。骨骼肌是 锻炼能力的关键成分通过其通过线粒体底物氧化产生ATP的能力 （即线粒体功能）。骨骼肌特性还会影响全身胰岛素敏感性， 影响代谢疾病的风险（例如2型糖尿病，肥胖）。新生的肌原性祖细胞是一个 骨骼肌肉可塑性的关键成分在锻炼时响应于运动，自我更新和通过 关于对女儿人群的表观遗传修饰。微薄的证据表明这些祖细胞是 通过生活方式干预措施坦白了随后的代谢改编的“印象”。提出的研究 将填补我们的知识空白，并直接评估运动训练的能力印刷肌祖先 细胞以提高运动能力并降低代谢疾病的风险。主要 本提案的目标是利用Motrpac父母项目并确定的独特能力 短期（三个月）和终身（运动员）有氧训练（AT）和阻力训练（RT） 通过表观遗传调节 骨骼肌祖细胞中新型运动反应基因的（DNA甲基化，RNA表达）。我们的 次要目标是建立来自Motrpac的人类原发性骨骼肌细胞（HSKMC）培养库 可以用于将来的机械审讯。我们假设运动训练会印记 通过新运动的表观遗传调节，骨骼肌祖细胞中的代谢特性 AT和RT之间会有所不同的响应基因。我们将从肌肉活检中建立HSKMC培养物 325个人（在RT，对照组）进行三个月的干预和75名运动员（在 和RT）和评估胰岛素作用（胰岛素刺激的糖原合成，胰岛素信号转导）， 线粒体功能（使用碳水合物和脂肪酸底物的O2消耗）​​，DNA甲基化和 RNA表达式（RNASEQ）具有相关途径富集分析。目标1的既定目的是 确定短期和终身和RT的独特能力，以烙印钥匙肌细胞代谢 通过运动反应基因的表观遗传调节特性（胰岛素敏感性，线粒体功能）。 DNA甲基化和RNASEQ数据的整合将识别新的运动反应基因 在体外的基因操纵以确定其对规定的代谢终点的影响。明确的目的 AIM 2是创建一个HSKMC存储库，以进行未来的调查。拟议研究的发现将 提供前所未有的机械洞察力，了解锻炼训练能够召集“代谢记忆”的能力 通过对特定运动反应基因的表观遗传修改并为后续运动提供信息 与优化锻炼中获得的健康益处相关的处方。