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 characterize iron-associated sensitivity and transcriptional dysregulation in cultured myoblasts from patients with COPD cachexia. Elucidating mechanisms of mitochondrial dysfunction in COPD cachexia has the potential to aid the development of therapeutics targeting mitochondrial oxidative stress. We will also establish a COPD cachexia myoblast assay of great utility for screening known and novel compounds with the potential to reverse or attenuate cachexia.
/ PUBLIC HEALTH RELEVANCE STATEMENT 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. Elucidating mechanisms of mitochondrial dysfunction in COPD cachexia has the potential to aid the development of therapeutics targeting mitochondrial oxidative stress.
