Skeletal muscle adaptation to hypoxia

描述（由申请人提供）：研究表明，缺氧可能对骨骼肌线粒体功能有害。例如，高海拔登山者呈现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描述。在2型糖尿病患者的肌肉活检中也出现了相同的线粒体减少模式，最近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展的可能触发因素。在慢性阻塞性肺疾病（COPD）患者中也观察到线粒体异常，COPD是一种以缺氧为显著特征的疾病。因此，研究线粒体！低氧条件下的变化不仅与高原适应有关，而且与低氧可能起致病作用的疾病状态有关。本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常压缺氧水平的久坐小鼠，以避免混淆因素，如缺氧水平和体力活动。我们将测试的假设，缺氧将减少线粒体生物因子的表达和蛋白质水平，特别是PGC-1a。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！在缺氧条件下的生物因子，使用标准的分子生物技术。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PGC-1a与白藜芦醇的药理学激活将逆转骨骼肌中缺氧诱导的线粒体变化。了解缺氧过程中线粒体的变化将有助于我们阐明其在2型糖尿病和COPD等疾病发病机制中的潜在作用，以开发新的治疗策略。

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.