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

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

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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）：已经表明缺氧可能对骨骼肌线粒体功能有害。例如，高海拔登山者会减少亚属膜的rnitochrial含量。但是，尚未描述基于这种现象的确切机制。糖尿病患者2型糖尿病患者的肌肉活检和糖尿病患者的最新基因表达研究得出的结论是，缺氧可能是发展代谢综合征的可能触发的可能触发的基因表达研究。在患有慢性阻塞性肺疾病（COPD）的患者中，线粒体异常也可以观察到这种情况，这种情况是缺氧是显着特征的。因此，线粒体的研究！低氧条件下的变化不仅与高海拔适应性有关，而且与缺氧可能发挥致病作用的疾病状态有关。该研究的总体目的是定义在低氧条件下骨骼肌氧化能力降低的机制。我们将使用暴露于稳定水平正常的缺氧水平的久坐小鼠，以避免混淆因素，例如缺氧水平和体育活动。我们将检验以下假设：缺氧将降低线粒体生物因子（尤其是PGC-1A）的表达和蛋白质水平。在特定目标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生物因子。特定目标2将评估低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。在特定的目标3中，我们将测试使用白藜芦醇的PGC-1A的药理激活将逆转骨骼肌中缺氧诱导的线粒体变化。在缺氧过程中发生的线粒体变化的理解将有助于我们阐明其在疾病的发病机理中的潜在作用，例如2型糖尿病和COPD，以制定新的治疗策略。