There is a growing recognition that chronic obstructive pulmonary disease (COPD) is a condition that involves multiple organs and systems.¹ In addition to emphysema and airway inflammation and remodelling, COPD is associated with various local and systemic complications including cachexia, weight loss, osteoporosis, muscle wasting, heart failure, atherosclerosis, dementia, depression, and cancer.^1–3 Strikingly, these extrapulmonary manifestations of COPD account for the vast majority of morbidity and mortality in COPD patients.^4,5 Treatments that modify these complications may improve survival in patients with COPD,^4,6 whereas treatments that exclusively target the airways generally do not.^5,7

SKELETAL MUSCLE DYSFUNCTION

One of the important extrapulmonary manifestations of COPD is skeletal muscle dysfunction and wasting.¹ With increasing severity of disease, patients with COPD lose muscle bulk, especially in their thighs and upper arms. Over time, these patients lose exercise endurance and complain of fatigue and dyspnoea with only a minimal degree of exertion.⁸ These symptoms curtail their ability to exercise and compromise their cardiac fitness, which further limits their exercise tolerance, creating a vicious downward spiral that can eventually lead to generalised debility and immobility.⁹ Not surprisingly, skeletal muscle dysfunction contributes to reduced health status of patients with COPD and substantially increases the risk of mortality, independent of traditional markers of COPD mortality such as baseline lung function, age, and cigarette smoking.^10,11 Encouragingly, early interventions with exercise programmes may restore some of the lost health status related to muscle dysfunction and increase patients’ exercise tolerance and stamina.⁷

Despite the importance of skeletal muscle performance in COPD morbidity and mortality, the pathophysiological mechanisms responsible for the muscle failure remain largely a mystery. Clearly, with advancing disease, skeletal muscle mass …