Skeletal muscle adaptation to hypoxia

骨骼肌对缺氧的适应

基本信息

批准号：
7487711
负责人：
Jorge Luis Gamboa
金额：
$ 2.81万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7487711
关键词：
Affect Altitude Biochemical Biogenesis Biopsy Blood flow Brain Cell Hypoxia Chronic Chronic Obstructive Airway Disease Citric Acid Cycle Comprehension Condition Cultured Cells DNA Development Disease Electrons Environment Enzymes Exercise Gene Expression Genes Genetic Transcription Health Heart Hematocrit procedure Human Hyperventilation Hypoxia Kidney Limb structure Lung diseases Malignant neoplasm of kidney Measures Messenger RNA Metabolic Metabolic syndrome Mitochondria Molecular Biology Techniques Mus Muscle Muscle Mitochondria Non-Insulin-Dependent Diabetes Mellitus Nuclear Numbers Oxidative Phosphorylation Oxygen Partial Pressure Pathogenesis Pathway interactions Patients Pattern Peroxisome Proliferators Phosphorylation Physical activity Play Proteins Purpose Rate Renal carcinoma Respiration Resveratrol Role Sea Skeletal Muscle Standards of Weights and Measures Techniques Testing Tissues Western Blotting cancer cell cofactor density diabetic enzyme activity factor A hypoxia inducible factor 1 insight mRNA Expression novel therapeutics nuclear respiratory factor prevent protein expression receptor research study sedentary transcription factor

项目摘要

DESCRIPTION (provided by applicant): It has been shown that hypoxia could be detrimental for skeletal muscle mitochondria function. For instance, high altitude mountaineers present a reduction in subsarcolemmal rnitochondrial content; however, the exact mechanism that underlies this phenomenon has not been described. The same pattern of nitochondrial reduction has also been in muscle biopsies of patients with diabetes mellitus type 2 and a recent gene expression study in diabetic patients concluded that hypoxia may be a possible trigger for the development of metabolic syndrome. Mitochondrial abnormalities are also observed in patients with chronic obstructive pulmonary disease (COPD), a condition where hypoxia is prominent feature. Thus, the study of mitochondria! changes under hypoxic conditions is not only relevant to high altitude adaptation but to diseases states where hypoxia may play a pathogenic role. The overall objective of the study is to define the mechanisms that underlie the reduction of mitochondria) oxidative capacity in skeletal muscles under hypoxic conditions. We will use sedentary mice exposed to steady level of normobaric hypoxia to avoid confounding factors such as the hypoxia level and the physical activity. We will test the hypothesis that hypoxia will reduce the expression and protein levels of mitochondrial biogenic factors, particularly PGC-1a. In specific aim 1 we will evaluate the gene expression and protein level of the mitochondria! biogenic factor under hypoxic conditions, using the standard molecular biology techniques. Specific Aim 2 will evaluate the changes of mitochondrial oxidative capacity under hypoxic conditions. Mitochondrial respiration and enzymes activities will be measured for this purpose. In Specific Aim 3 we will test that the pharmacological activation of PGC-1a with resveratrol will reverse the hypoxic-induced mitochondrial changes in skeletal muscle. The comprehension of the mitochondria) changes that occur during hypoxia will help us to elucidate its potential role on the pathogenesis of diseases, such as diabetes mellitus type 2 and COPD, in order to develop new therapeutic strategies.

描述（由申请人提供）：已表明缺氧可能对骨骼肌线粒体功能有害。例如，高海拔登山者的肌膜下线粒体含量减少；然而，这种现象背后的确切机制尚未被描述。 2 型糖尿病患者的肌肉活检也出现了同样的线粒体减少模式，最近一项针对糖尿病患者的基因表达研究得出结论，缺氧可能是代谢综合征发生的可能触发因素。在慢性阻塞性肺疾病（COPD）患者中也观察到线粒体异常，这是一种以缺氧为显着特征的疾病。因此，线粒体的研究！缺氧条件下的变化不仅与高海拔适应有关，而且与缺氧可能发挥致病作用的疾病状态有关。该研究的总体目标是确定缺氧条件下骨骼肌线粒体氧化能力降低的机制。我们将使用暴露于稳定水平的常压缺氧的久坐小鼠，以避免缺氧水平和体力活动等混杂因素。我们将检验缺氧会降低线粒体生物因子（尤其是 PGC-1a）的表达和蛋白质水平的假设。在具体目标 1 中，我们将评估线粒体的基因表达和蛋白质水平！使用标准分子生物学技术，在低氧条件下研究生物因素。具体目标2将评估缺氧条件下线粒体氧化能力的变化。为此目的将测量线粒体呼吸和酶活性。在具体目标 3 中，我们将测试白藜芦醇对 PGC-1a 的药理学激活是否会逆转骨骼肌中缺氧诱导的线粒体变化。了解缺氧期间发生的线粒体变化将有助于我们阐明其在 2 型糖尿病和慢性阻塞性肺病等疾病发病机制中的潜在作用，从而开发新的治疗策略。