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: 10180841
• 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/10180841
• 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; 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.

项目概要/摘要 确定运动益处的分子调控点是国家的高度优先事项，因为 开发有针对性的新型疗法的机会，使患有与缺乏活动相关的健康问题的人群受益 问题，包括 T2DM 和糖尿病前期，其特征是胰岛素抵抗 (IR)。 IR 最常见于 与肌肉减少症相关的老年人群。我们提出 PGC-1α4 (α4) 的新代谢调节作用， 一种肥大基因，通过抗阻运动（RE）增强。基于大量的初步数据，我们 假设 α4 与 PPARβ (Rβ) 协同作用，促进肌肉糖酵解和胰岛素敏感性 (IS) 以及增加肌肉质量和性能。根据我们新颖的初步数据，我们还将调查 RE 是否通过糖酵解蛋白的去乙酰化来增强肌肉糖酵解能力。 Rβ也减少 氧化应激不仅增强 IS，还有助于其他健康益处。基于新 mRNA 的数据 表明 RE 减少了蛋白质降解，这将在当前提案中进行研究。我们将 确定 3 个月的 RE 训练是否可以增强胰岛素敏感性以及肌肉性能和质量 IR人通过增强糖酵解、糖酵解蛋白脱乙酰化、减少蛋白质的途径 降解和增强合成以及改善氧化应激。我们将研究 48 名 50-75 岁的 IR 人士 每周 4 次阻力训练或久坐生活 3 个月之前和之后，并将它们与 精益是人。我们将在急性运动前后收集股外侧肌活检样本 混合餐后测量糖酵解、能量代谢物、糖原合成酶的标记物， 糖原含量、α4、Rβ、胰岛素信号蛋白和蛋白质组分析。我们还将测量以下标记 氧化应激，包括 8-OXO-dg（DNA 损伤的测量）、蛋白质氧化损伤以及随后的氧化损伤 肌肉蛋白降解，我们假设通过 RE 增强 Rβ 的抗氧化作用来减少肌肉蛋白降解 训练。我们还将使用稳定同位素标记的示踪剂对特定肌肉蛋白进行体内标记 确定 α4 诱导的肌肉肥大是否发生不仅可以通过减少降解，还可以通过 增强收缩蛋白的合成。尽管我们的初步细胞系研究提供了支持数据 α4和Rβ对IS和糖酵解的直接影响以及Rβ的抗氧化作用，这些直接影响 影响我们结果的基因无法从人类身上获得。因此我们将在小鼠模型中进行研究 与高脂肪饮食诱导的 IR 相比，表明 α4 增强 IS 和糖酵解，而 Rβ 减少氧化应激。我们 还将沉默小鼠肌肉的 α4 和 Rβ，以证实我们基于细胞的结果表明收缩诱导的 变化取决于 α4 和 Rβ。这些人类和动物研究共同将提供必要的 RE 如何增强 IS、糖酵解、减少氧化应激和促进肌肉的机制解释 IR 人群的表现和质量，从而极大地促进他们的健康和寿命。