PROJECT SUMMARY
Chronic obstructive pulmonary disease (COPD) is destruction of lung tissue and/or thickening of lung airways. It
is the fourth leading cause of death in the USA. COPD is progressive and characterized by chronic inflammation
and shortness of breath on exertion, which leads to physical inactivity and skeletal muscle dysfunction. Survival
rate in COPD is more closely associated with exercise capacity than the severity of lung disease. A key
determinant of exercise capacity is the ability of skeletal muscle mitochondria to sustain cellular energy delivery
(termed, oxidative capacity). We recently applied a noninvasive near-infrared light-based method to assess
muscle oxidative capacity in 245 smokers with and without COPD: the COPDGene ancillary Muscle Health
Study. We showed that severe COPD patients have a 40% lower muscle oxidative capacity than smokers or
never smokers with normal lung function. Yet, many questions remain about characteristics and mechanisms
behind the loss of muscle oxidative capacity in COPD. The current proposal will follow-up with 200 of the Muscle
Health Study participants to determine for the first time the rate of decline in lower limb skeletal muscle oxidative
capacity over 5 years. Using the individual genetics, triaxial accelerometer measured daily physical activity, body
composition measured by DXA, and 808 other clinical variables collected in the COPDGene parent study, we
will identify clinical, behavioral and genetic variables that associate with the 5-year decline in skeletal muscle
oxidative capacity. In addition, quadriceps muscle biopsy samples from 20 COPD patients with the fastest
decline and 20 with the slowest decline in muscle oxidative capacity, identified by the near-infrared based
noninvasive assessment, will be used to discover how gene expression is altered by the disease. DNA
methylation and expression of small and large RNAs, including small non-coding RNAs from the mitochondrial
genome (mitosRNAs), will be probed. These highly specific approaches will provide a detailed profile of
mitochondrial and nuclear genes and/or gene networks underlying the causes of derangements in the lower limb
skeletal muscles of COPD patients. The decline in muscle oxidative capacity impairs exercise tolerance and
predisposes patients to chronic diseases such as cardiovascular disease, diabetes and obesity, each of which
increases risk of premature death. The current proposal will be the first to determine how loss of muscle oxidative
capacity progresses in COPD, and answer fundamental questions about the nature of the associations among
mitochondrial dysfunction, sedentary lifestyle and poor outcomes in COPD patients. Our findings will guide
efforts to create new therapeutic strategies to prevent skeletal muscle dysfunction, increase autonomy, hospital
free survival and quality-of-life in COPD.