Phenotypes of Muscle Loss in Smokers

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PROJECT SUMMARY/ABSTRACT Chronic obstructive pulmonary disease (COPD) is a leading cause of death in the United States and worldwide. Decreased muscle mass is common in COPD and associates with lung disease severity, functional impairment, systemic inflammation, and all-cause mortality. Fat free mass index (FFMI), defined by the sum of whole-body lean muscle and bone mineral content adjusted for height in meters squared, is an accepted surrogate marker of whole-body muscle mass in COPD. FFMI associates with lung function and is an independent predictor of mortality in individuals with COPD who have normal BMI. However, most studies evaluating FFMI in COPD are cross-sectional and do not examine changes in FFMI over time. These longitudinal studies are critical to identify the clinical and molecular phenotype of individuals at greatest risk for disease morbidity and mortality. Additionally, most studies focused primarily on current and former smokers with airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) <0.70. Yet, smokers without airflow obstruction remain at risk for emphysema, respiratory symptoms, and respiratory exacerbations compared with the general population. Our preliminary data show that longitudinal muscle mass changes in smokers are not modified by airflow obstruction status, and that a subset of smokers both with and without airflow obstruction demonstrates a significant decrease in FFMI over time. In this study, we will leverage our well- characterized longitudinal cohort of current and former smokers with and without airflow obstruction who have serial clinical, physiologic, and radiographic data, FFMI data determined from readily available dual energy x-ray absorptiometry (DXA), and banked blood samples to test our primary hypotheses that distinct trajectories of muscle mass change are associated with specific clinical and molecular phenotypes and that rapid FFMI decline correlates with lung disease progression and functional impairments over time. In Aim 1, I will determine trajectories of FFMI change in smokers with and without airflow obstruction and identify important baseline clinical and molecular predictors of muscle loss trajectories. In Aim 2, I will compare longitudinal changes in lung function, emphysema, functional status, and circulating inflammatory proteins between smokers with rapid FFMI decline and smokers without rapid FFMI decline. This study proposal will provide important insight into the natural history of muscle loss in smokers with and without airflow obstruction and help establish specific clinical and molecular phenotypes associated with rapid muscle mass decline for targetable interventions in future studies. This training plan, combined with close mentorship and a robust research environment at the University of Pittsburgh, will facilitate my transition to a mentored Career Development Award and, ultimately, to an independent career as a physician-scientist.