PGC-1 & Muscle Mitochondrial Dysfunction in Diabetes

PGC-1

• 批准号: 8791895
• 负责人: LAWRENCE J MANDARINO
• 金额: $ 57.39万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791895
• 关键词: 5' Untranslated Regions; Acetylation; Acute; Affect; Agonist; Biopsy; Cardiovascular Diseases; Data; Diabetes Mellitus; Disease; Effectiveness; Event; Exercise; Family; Family member; Fibrates; Gemfibrozil; Gene Expression; Genes; Glucose; Goals; Health; Human; In Vitro; Individual; Insulin; Insulin Resistance; Knock-out; Lipids; Messenger RNA; MicroRNAs; Mitochondrial Proteins; Molecular; Mus; Muscle; Myelogenous; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Patients; Phosphorylation; Plasma; Post-Translational Protein Processing; Proteins; Public Health; RELA gene; Resistance; Response Elements; Rest; SP1 gene; Skeletal Muscle; System; Testing; Translations; Untranslated Regions; Work; Zinc Fingers; diabetic; diabetic patient; human disease; improved; insulin sensitivity; member; mitochondrial dysfunction; novel; overexpression; programs; research study; response; transcription factor; transcriptomics; volunteer

DESCRIPTION (provided by applicant): We discovered a phenomenon called "exercise resistance", where insulin resistant individuals do not respond normally to a single bout of exercise with respect to expression of PGC-1α and other genes). To generate hypotheses regarding why this happens, normal glucose tolerant volunteers had one exercise bout with muscle biopsies at rest and 30 min after exercise. We found that 216 mRNAs corresponding to 130 genes changed significantly after exercise. Transcriptional regulators were significantly over-represented. Analysis of the 5' untranslated regions of the affected genes showed significant enrichment in transcription factor response elements, including motifs for NFKB1, RELA, SP1/KLF family, and EGR1. Analysis of the 5' UTR of these transcription factors revealed one common potential transcriptional regulator, myeloid zinc finger 1 (MZF1). The change in MZF1 expression after exercise was positively correlated with insulin sensitivity. MZF1 expression also was increased markedly in insulin resistant obese and diabetic patients, suggesting dysregulation of this system. We used these experiments to conduct a closer examination of more factors that regulate mRNA and protein abundance. Among these, microRNAs (miRNAs) regulate much of gene expression and translation events. Preliminary Data shows that, in healthy people, exercise increases microRNAs that target FOXO1 mRNA, and FOXO1 protein is increased in obese and type 2 diabetic muscle, accompanied by decreased FOXO1 phosphorylation, indicating potential activation of the FOXO1 transcriptional program in insulin resistant muscle. There are few data on how exercise and insulin sensitivity interact in skeletal muscle with regard to global miRNA expression events in human muscle. Finally, the expression of PPARα and its downstream targets decreased 30 minutes after acute exercise in an insulin sensitivity-related manner. In mice PPARα overexpression in muscle worsens and PPARα knockout improves insulin sensitivity. Thus, PPARα activation in muscle may detrimental to insulin sensitivity, and begs the question of whether treatment with fibrates to lower plasma lipids could work against insulin sensitizing effects of exercise in skeletal muscle. The overall goal of this project is to understand the interplay between insulin sensitivity and the gene expression response to exercise in skeletal muscle. Although substantial data is available in mice and in vitro systems, the applicability of these data to human disease is required. We propose: 1. To determine whether the transcription factor expression response to exercise is dysregulated in muscle from type 2 diabetic patients; 2. To determine how insulin resistance changes the response of posttranslational modifications of SP1/KLF family and MZF1 transcription factors to acute exercise in muscle from type 2 diabetic patients; 3. To define the response of miRNAs to acute exercise in healthy and insulin resistant muscle from obese and type 2 diabetic patients; 4. To determine whether treatment with PPARα agonist fibrate derivatives suppresses the normal gene expression response to acute exercise.

描述（由适用提供）：我们发现了一种称为“运动耐药性”的现象，其中胰岛素耐药的个体在PGC-1α和其他基因的表达方面对单次运动没有正常反应）。为了产生有关发生这种情况的假设，正常的葡萄糖耐受性志愿者在休息时和运动后30分钟内进行了一次运动。我们发现，运动后，与130个基因相对应的216个mRNA发生了重大变化。转录调节器的代表性大大过多。对受影响基因的5'非翻译区域的分析表明，转录因子响应元件的富集显着富集，包括NFKB1，RELA，SP1/KLF家族和EGR1的基序。对这些转录因子的5'UTR的分析表明，一个常见的潜在转录调节剂髓样锌指1（MZF1）。运动后MZF1表达的变化与胰岛素敏感性正相关。在胰岛素抵抗肥胖和糖尿病患者中，MZF1表达也显着增加，表明该系统失调。我们使用这些实验对调节mRNA和蛋白质丰度的更多因素进行了仔细研究。其中，microRNA（miRNA）调节了许多基因表达和翻译事件。初步数据表明，在健康的人中，运动增加了肥胖和2型糖尿病肌肉的靶向FOXO1 mRNA和FOXO1蛋白的microRNA，通过增加FOXO1磷酸化来实现，表明胰岛素抵抗肌肉中FOXO1转录程序的潜在激活。关于运动和胰岛素敏感性如何在人类肌肉中的全球miRNA表达事件中相互作用的数据很少。最后，急性运动后30分钟以胰岛素敏感性相关的方式，PPARα及其下游靶标的表达降低。在小鼠中，肌肉中的PPARα过表达恶化，PPARα基因敲除可以提高胰岛素敏感性。这是肌肉中的PPARα激活可能会损害胰岛素敏感性，并开始一个问题：纤维化治疗是否可以降低血浆脂质，可以抵抗运动在骨骼肌中运动的胰岛素敏感性影响。该项目的总体目标是了解胰岛素敏感性与骨骼肌运动的基因表达反应之间的相互作用。尽管在小鼠和体外系统中可以使用大量数据，但这些数据对人类疾病的适用性仍需要。我们建议：1。确定2型糖尿病患者的肌肉中对运动的转录因子表达反应是否失调； 2。确定胰岛素抵抗如何改变SP1/KLF家族和MZF1转录因子对2型糖尿病患者肌肉急性运动的翻译后修饰的反应； 3。定义miRNA对肥胖和2型糖尿病患者耐胰岛素肌肉的急性运动的反应； 4。确定用PPARα激动剂纤维化衍生物处理是否会抑制正常基因表达对急性运动的反应。