Skeletal muscle adaptation to hypoxia

描述(由申请人提供)：已有研究表明，缺氧可能损害骨骼肌线粒体功能。例如，高海拔登山者表现出肌膜下线粒体含量的减少；然而，这种现象背后的确切机制尚未被描述。在2型糖尿病患者的肌肉活检组织中也存在同样的线粒体减少模式，最近一项对糖尿病患者的基因表达研究得出结论，低氧可能是代谢综合征发生的一个可能触发因素。慢性阻塞性肺疾病(COPD)患者也可观察到线粒体异常，这种疾病以缺氧为显著特征。因此，线粒体的研究！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。这项研究的总体目标是确定在低氧条件下骨骼肌线粒体氧化能力降低的机制。我们将使用久坐不动的小鼠暴露在稳定的常压低氧中，以避免低氧水平和体力活动等混杂因素。我们将检验低氧会降低线粒体生物起源因子，特别是PGC-1a的表达和蛋白水平的假设。在特定的目标1中，我们将评估线粒体的基因表达和蛋白水平！低氧条件下的生物因子，使用标准的分子生物学技术。特异性目标2将评估线粒体在低氧条件下氧化能力的变化。为此，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的药理激活将逆转缺氧诱导的骨骼肌线粒体变化。了解线粒体在缺氧过程中的变化将有助于阐明其在2型糖尿病和慢性阻塞性肺疾病等疾病发病机制中的潜在作用，从而开发新的治疗策略。

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.