COPD cachexia: deciphering the impact of antioxidants, iron and mitochondrial function using 'omics approaches

总结 慢性阻塞性肺疾病（COPD）是美国第四大死亡原因 尽管医学进步了，但死亡率仍在上升。恶病质是肌肉萎缩的一种形式， 使人衰弱的合并症，其患病率随着COPD的严重程度而增加。但是，恶病质仍然发生在 病情较轻的COPD患者。恶病质最常被认为与癌症有关。然而，在这方面， 从人群患病率来看，COPD恶病质患者多于癌症恶病质患者。然而 很少有研究调查COPD恶病质的病因，强调需要 COPD恶病质和体重减轻的研究。积累的数据包括我们自己的数据都指出了铁的作用 毒性在COPD恶病质病因学中的作用。血红素是线粒体细胞色素的重要组成部分 提供对活性氧物质（ROS）的保护。血红素生物合成的缺陷导致游离血红素的积累， 铁、ROS和线粒体功能障碍。游离铁的积累导致铁毒性和ROS的产生 特别是在缺乏足够的抗氧化剂如维生素E摄入的情况下。因此，我们的总体 一种假说是COPD恶病质中的铁毒性是由受损的抗氧化剂和线粒体功能驱动的。这 研究有三个具体目标：1）确定基因组变异是否与吸收相关， 维生素E的调节在COPD恶病质中更常见; 2）评估受试者的血浆维生素E是否 COPD恶病质患者与线粒体功能受损相关;探索性目的） 成肌细胞中铁诱导的转录失调标记保留在转录组学标记中 与COPD恶病质相关。阐明线粒体 COPD恶病质中的功能障碍有可能帮助开发靶向线粒体的治疗方法 氧化应激作为未来的研究，我们计划测试是否'组学区域和代谢物确定为 与COPD恶病质直接影响途径涉及维生素E和线粒体功能 使用成肌细胞或其它适当系统中的靶向测定。

SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the United States with mortality continuing to rise despite advances in medicine. Cachexia, a form of muscle wasting, is a debilitating co-morbidity whose prevalence increases with severity of COPD. But, cachexia still occurs among COPD patients with milder disease severity. Cachexia is most often thought of with respect to cancer. However, by population prevalence there are more COPD patients with cachexia than cancer patients with cachexia. Yet there have been few studies investigating the etiology of COPD cachexia underscoring the need for investigations of COPD cachexia and weight-loss. Accumulating data including our own points to a role for iron toxicity in the etiology of COPD cachexia. Heme is an essential component of mitochondrial cytochromes providing protection from reactive oxygen species (ROS). Defects in heme biosynthesis cause buildup of free iron, ROS and mitochondrial dysfunction. Buildup of free iron leads to iron toxicity and production of ROS particularly in the absence of adequate intake of antioxidants such as Vitamins E. As such, our overarching hypothesis is iron toxicity in COPD cachexia is driven by impaired antioxidant and mitochondrial function. This study has three specific aims: 1) To determine whether genomic variation associated with the absorption and regulation of Vitamin E is more common in COPD cachexia; 2) To assess whether plasma Vitamin E in subjects with COPD cachexia are associated with impaired mitochondrial function; Exploratory Aim) To test whether iron induced transcriptional dysregulation signatures in myoblasts are preserved in transcriptomics signatures associated with COPD cachexia in skeletal muscle biopsies. Elucidating mechanisms of mitochondrial dysfunction in COPD cachexia has the potential to aid the development of therapeutics targeting mitochondrial oxidative stress. As future research, we plan to test whether ‘omic regions and metabolites identified as associated with COPD cachexia directly effect pathways involved with Vitamin E and mitochondrial function using targeted assays in myoblasts or other appropriate systems.