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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘