Mechanisms by which strength training ameliorates the Metabolic Syndrome

力量训练改善代谢综合症的机制

• 批准号: 8006750
• 负责人: CHARLES A STUART
• 金额: $ 0.67万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-20 至 2010-04-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006750
• 关键词: 5' -AMP-activated protein kinase; Adult; Aerobic; Affect; Anatomy; Back; Behavior Therapy; Bicycling; Biochemical; Biogenesis; Blood Glucose; Blood flow; Body Composition; Central obesity; Clinical; Clinical Research; Coronary heart disease; Data; Development; Diabetes Mellitus; Diagnosis; Electron Transport; Elements; Enzymes; Epidemic; Euglycemic Clamping; Evaluation; Excess Mortality; Exercise; Fatty acid glycerol esters; Fiber; Gene Targeting; Genes; Glucose; Glucose Clamp; Glucose Transporter; Goals; Hexose Transporter; Human; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Hypertension; Hypertrophy; Immunoblotting; Insulin; Insulin Resistance; Intramuscular; Knowledge; Lead; Life Expectancy; Life Style; Link; Measures; Metabolic syndrome; Mitochondria; Mitochondrial DNA; Molecular; Muscle; Muscle Cells; Muscle Contraction; Muscle Fibers; Needle biopsy procedure; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Oxygen; PTGS1 gene; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Persons; Pharmaceutical Preparations; Pilot Projects; Prediabetes syndrome; Prevalence; Prevention; Protein Biosynthesis; Protein Isoforms; Protein Kinase; Recruitment Activity; Regulator Genes; Regulatory Pathway; Research; Research Personnel; Resistance; Risk; Secure; Sirolimus; Study Subject; Subcellular Fractions; System; Techniques; Testing; Thigh structure; Time; Tobacco use; Training; United States; White Fiber; White Muscle Fibers; blood glucose regulation; cytochrome c; diabetes prevention program; experience; fasting plasma glucose; glucose uptake; high risk; improved; insulin sensitivity; mTOR protein; novel; programs; protein metabolism; public health relevance; sedentary; strength training; tool; treatment strategy; uptake; vastus lateralis

DESCRIPTION (provided by applicant): Life style alterations can be powerful deterrents to developing type 2 diabetes and are cornerstones of the treatment of this condition. Both aerobic and resistance exercise improve diabetes blood glucose control and insulin resistance. These two types of exercise appear to exert their effects on different muscle fiber types - red for endurance and white for strength. Similar to the effects of endurance exercise training, strength training increases muscle glucose transporter isoform 4 (GLUT4), but in contrast, mitochondria numbers do not increase. We hypothesize (1) that strength training in persons with pre-diabetes may be effective in reversing insulin resistance by novel mechanisms that are distinct from the endurance training-induced mitochondrial biogenesis. We further hypothesize (2) that resistance exercise training enhances whole body insulin action primarily by increasing the white fiber size via the protein kinase mammalian target of rapamycin (mTOR) and improves insulin-stimulated glucose uptake by increased GLUT4 expression primarily in white fibers of the trained muscles. In this application, we will perform eight weeks of progressive strength training on ten subjects with the Metabolic Syndrome who are at high risk for developing type 2 diabetes and on ten sedentary control subjects. This project builds on our experience with a study of focused resistance training whose results are presented in this application. In this pilot study, subjects exercised on stationary bicycles for six weeks causing muscle GLUT4 and phopho-mTOR to increase substantially, but maximal oxygen uptake (VO2max), phospho-AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-3 co-activator (PGC-11), and mitochondrial markers did not change. Our hypotheses will be tested by two Specific Aims. (1) Subjects at high risk for diabetes will undergo progressively increasing intensity resistance exercise training and increased strength and improved insulin responsiveness will both be quantified to demonstrate significant benefit, and (2) quantify the effect of resistance exercise training on anatomic and functional adaptation in muscle. We will characterize fiber type, fiber size, fiber-specific changes in mitochondrial DNA and enzymes, fiber-specific changes in the principle glucose transporters in muscle (GLUT4, GLUT5, and GLUT12), and evaluate changes in two distinct intramuscular pathways (AMPK, mTOR) and regulatory factors (PGC-11, PPAR3, PPAR4) using immunoblots of muscle subcellular fractions and immunohistochemical techniques. These evaluations of molecular mechanisms will also include assessing changes in full human Affymetrix gene array data that may move us to new potential resistance training-regulated gene targets. It is the long-term goal of this team of investigators to understand the interplay between life style changes and pharmacological agents in the prevention and treatment of diabetes. Our results will facilitate the development of more effective clinical options to turn back the epidemic of obesity and diabetes in the United States. PUBLIC HEALTH RELEVANCE: Prevention and treatment strategies for diabetes use exercise as the cornerstone. Even though endurance training and strength training both improve insulin resistance, strength training may be better suited for persons at risk for type 2 diabetes. We will expand our pilot studies of muscle adaptation induced by resistance exercise training to determine the biochemical mechanisms that will cause people with the Metabolic Syndrome to secure major benefit from intense strength training.

描述（由申请人提供）：生活方式的改变可能是发展2型糖尿病的强大威慑力，也是治疗这种疾病的基石。有氧运动和抗阻运动都能改善糖尿病患者的血糖控制和胰岛素抵抗。这两种类型的运动似乎对不同的肌肉纤维类型产生影响-红色代表耐力，白色代表力量。与耐力运动训练的效果类似，力量训练增加了肌肉葡萄糖转运体亚型4（GLUT 4），但相比之下，线粒体数量并没有增加。我们假设（1）糖尿病前期患者的力量训练可能通过与耐力训练诱导的线粒体生物发生不同的新机制有效逆转胰岛素抵抗。我们进一步假设（2）抗阻运动训练主要通过蛋白激酶哺乳动物雷帕霉素靶点（mTOR）增加白色纤维大小来增强全身胰岛素作用，并通过增加主要在训练肌肉的白色纤维中的GLUT 4表达来改善胰岛素刺激的葡萄糖摄入。在本申请中，我们将对10名患有代谢综合征的受试者进行8周的渐进式力量训练，这些受试者具有患2型糖尿病的高风险，并对10名久坐不动的对照受试者进行训练。这个项目建立在我们的经验与集中阻力训练的研究，其结果是在这个应用程序。在这项初步研究中，受试者在固定自行车上锻炼六周，导致肌肉GLUT 4和磷酸mTOR大幅增加，但最大摄氧量（VO 2 max），磷酸AMP激活蛋白激酶（AMPK），过氧化物酶体增殖物激活受体-3共激活剂（PGC-11）和线粒体标志物没有变化。我们的假设将通过两个具体目标进行检验。(1)糖尿病高风险受试者将接受强度逐渐增加的抗阻运动训练，并将对增加的力量和改善的胰岛素反应性进行量化，以证明显著的益处，以及（2）量化抗阻运动训练对肌肉解剖和功能适应的影响。我们将表征纤维类型，纤维大小，线粒体DNA和酶的纤维特异性变化，肌肉中主要葡萄糖转运蛋白（GLUT 4，GLUT 5和GLUT 12）的纤维特异性变化，并使用肌肉亚细胞组分的免疫印迹和免疫组织化学技术评估两种不同肌内途径（AMPK，mTOR）和调节因子（PGC-11，PPAR 3，PPAR 4）的变化。这些分子机制的评估还将包括评估完整的人类Affyphin基因阵列数据的变化，这些数据可能会使我们转向新的潜在的抵抗训练调节基因靶点。这是这个研究小组的长期目标，以了解生活方式的变化和药物之间的相互作用，在预防和治疗糖尿病。我们的研究结果将有助于开发更有效的临床选择，以扭转美国肥胖和糖尿病的流行。公共卫生相关性：糖尿病的预防和治疗策略以运动为基石。尽管耐力训练和力量训练都能改善胰岛素抵抗，但力量训练可能更适合有2型糖尿病风险的人。我们将扩大抗阻运动训练诱导的肌肉适应性的试点研究，以确定代谢综合征患者从高强度训练中获得主要益处的生化机制。