Molecular Mechanisms of Exercise Benefits to Insulin Resistant People

运动对胰岛素抵抗人群有益的分子机制

• 批准号: 10417138
• 负责人: K Sreekumaran Nair
• 金额: $ 60.23万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417138
• 关键词: Acute; Aerobic Exercise; Animals; Antioxidants; Attenuated; Biopsy Specimen; Cell Line; Cell Respiration; Cells; Contractile Proteins; DNA; DNA Damage; Data; Deacetylation; Elderly; Energy Metabolism; Enzymes; Exercise; Fatigue; GDF8 gene; GLUT 4 protein; Gene Expression; Genes; Glucose; Glycogen; Glycogen (Starch) Synthase; Glycolysis; Glycolysis Pathway; Health; Health Benefit; Heat shock proteins; High Fat Diet; Hour; Human; Hypertrophy; IGF1 gene; Individual; Insulin; Insulin Resistance; Label; Leg; Life; Longevity; Measures; Mediating; Messenger RNA; Metabolic; Molecular; Molecular Target; Morbidity - disease rate; Mus; Muscle; Muscle Contraction; Muscle Fatigue; Muscle Proteins; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; OPA1 gene; Older Population; Outcome; Oxidative Stress; PPAR-beta; Pathway interactions; Performance; Persons; Phenotype; Phosphorylation; Population; Prediabetes syndrome; Protein Biosynthesis; Proteins; Proteome; Quality of life; Regulation; Role; SOD2 gene; Signaling Protein; Skeletal Muscle; Stable Isotope Labeling; Thinness; Time; Tracer; base; blood glucose regulation; catalase; exercise training; glucose uptake; healthspan; improved; in vivo; insight; insulin sensitivity; insulin sensitivity/resistance; insulin signaling; interest; mortality; mouse model; muscle form; muscle hypertrophy; muscle strength; new therapeutic target; novel; novel therapeutic intervention; overexpression; oxidative damage; protein degradation; protein metabolism; resistance exercise; sarcopenia; sedentary; strength training; superoxide dismutase 1; vastus lateralis; vector

PROJECT SUMMARY/ABSTRACT Identification of the molecular regulatory points of exercise benefits is of high national priority because of the opportunity to develop targeted novel therapeutics benefiting populations suffering from inactivity-related health problems, including T2DM and pre-diabetes, characterized by insulin resistance (IR). IR is most prevalent in the older population associated with sarcopenia. We propose novel metabolic regulatory role of PGC-1α4 (α4), a hypertrophy gene, enhanced by resistance exercise (RE). Based on substantial preliminary data, we hypothesize that α4, in cooperation with PPARβ (Rβ), promotes muscle glycolysis and insulin sensitivity (IS) as well as increasing muscle mass and performance. Based on our novel preliminary data we will also investigate whether by deacetylation of glycolytic proteins, RE enhances muscle glycolytic capacity. Rβ also reduces oxidative stress that not only enhances IS but also contributes to other health benefits. New mRNA based data indicates that RE reduces protein degradation which will be investigated in the current proposal. We will determine whether 3 months of RE training enhances insulin sensitivity and muscle performance and mass in IR people through pathways of enhanced glycolysis, deacetylation of glycolytic proteins reducing protein degradation and enhancing synthesis and ameliorating oxidative stress. We will study 48 IR people 50-75 yrs before and after 3 months of either 4-times/week resistance training or sedentary life and compare them with lean IS people. We will collect vastus lateralis muscle biopsy samples before and after an acute exercise bout and following a mixed meal to measure markers of glycolysis, energy metabolites, glycogen synthase, glycogen content, α4, Rβ, insulin signaling proteins and proteome analysis. We will also measure markers of oxidative stress including 8-OXO-dg (measure of DNA damage), oxidative damage to proteins and subsequent muscle protein degradation, which we hypothesize is reduced by increased anti-oxidant effect of Rβ with RE training. We also will use in vivo labeling of specific muscle proteins utilizing stable isotope labeled tracers to determine whether α4 induced muscle hypertrophy occurs not only by reducing degradation but also by enhancing contractile protein synthesis. Although our preliminary cell line studies provide supporting data on direct effects of α4 and Rβ on IS and glycolysis and on the anti-oxidant effect of Rβ, direct effects of these genes on our outcomes cannot be obtained in humans. Therefore we will perform studies in a mouse model with high-fat diet-induced IR to show that α4 enhances IS and glycolysis and Rβ reduces oxidative stress. We also will silence α4 and Rβ of mouse muscle to confirm our cell based results showing that contraction-induced changes are dependent on α4 and Rβ. Together these human and animal studies will render the necessary mechanistic explanation on how RE enhances IS, glycolysis, reduces oxidative stress and promote muscle performance and mass in IR people, thus substantially contributing to their health and life spans.

项目摘要/摘要 鉴定分子调节锻炼点的益处是高国家优先事项，因为 开发有针对性的新疗法的机会有益于患有与活动相关的健康的人群 包括T2DM和糖尿病前的问题，其特征是胰岛素抵抗（IR）。 IR最普遍 与肌肉减少症相关的老年人。我们提出了PGC-1α4（α4）的新型代谢调节作用 肥大基因，通过抵抗运动（RE）增强。基于大量初步数据，我们 假设α4与PPARβ（Rβ）合作促进了肌肉糖酵解和胰岛素敏感性（IS） 以及增加肌肉质量和性能。根据我们的新型初步数据，我们还将调查 无论是通过脱乙酰基化糖酵解蛋白，都可以增强肌肉糖酵解能力。 Rβ也减少了 不仅增强的氧化压力，而且还有助于其他健康益处。新的基于mRNA的数据 表明RE会减少蛋白质降解，这将在当前的建议中进行研究。我们将 确定3个月的重新训练增强功能是否胰岛素敏感性和肌肉性能以及质量 通过增强糖酵解的途径，IR人员，糖酵解蛋白的脱乙酰化减少蛋白 降解并增强合成和改善氧化物应激。我们将学习48人50 - 75年 在3个月之前和之后进行4次/周的抵抗训练或久坐的生活，并将其与 瘦是人。在急性运动之前和之后，我们将收集大量的外侧肌肉活检样本 并在混合餐后测量糖酵解，能量代谢产物，糖原合酶， 糖原含量，α4，Rβ，胰岛素信号蛋白和蛋白质组分析。我们还将测量 氧化应激，包括8-oxo-DG（DNA损伤的度量），蛋白质的氧化损伤以及随后的 肌肉蛋白降解，我们假设的肌肉蛋白质通过Rβ的抗氧化作用增加而降低 训练。我们还将使用稳定的同位素标记示踪剂的特定肌肉蛋白的体内标记 确定α4是否诱导肌肉肥大不仅通过减少降解，还会发生 增强收缩蛋白合成。尽管我们的初步细胞系研究提供了有关的支持数据 α4和Rβ对IS和糖酵解以及Rβ的抗氧化作用的直接作用，这些直接作用的直接作用 关于我们结果的基因无法在人类中获得。因此，我们将在鼠标模型中进行研究 使用高脂饮食引起的IR，表明α4增强是IS，糖酵解和Rβ减少了氧化应激。我们 还将使小鼠肌肉的α4和Rβ保持沉默，以确认我们的基于细胞的结果表明合同诱导 变化取决于α4和Rβ。这些人类和动物研究将共同​​使必要 关于糖酵解，减少氧化应激并促进肌肉的机理解释 IR人员的表现和质量，因此有助于其健康和生活跨度。