Peripheral muscle weakness is a common and serious complication of chronic obstructive pulmonary disease (COPD), which precedes loss of fat-free mass and is an independent predictor of mortality in patients with Global Initiative for COPD grade III or IV disease 1. Current treatment options for muscle weakness are limited to exercise and supplemental feeding for cachectic patients. However, this approach is not effective in all individuals and the development of drugs that could be used as adjunctive therapies in the treatment of muscle weakness is hindered by a lack of knowledge of the molecular mechanisms responsible for the muscle dysfunction.
Two types of muscle abnormality are observed in the quadriceps muscle of patients with moderate and severe COPD. Atrophy occurs, particularly of the anaerobic type-IIx fibres, and is manifest as a loss of muscle strength. In addition, loss of muscle oxidative capacity arises from the depletion of aerobic type-I fibres and a reduction in mitochondria and oxidative enzymes within both type-I and -IIa fibres, resulting in decreased muscle endurance. At present, it is unclear whether these two processes are linked, for example whether atrophy of type-IIx fibres drives a switch of type-I to type-II fibres, or whether these processes occur independently. Animal studies have identified an array of pathways that could be involved in the development of muscle atrophy or loss of oxidative capacity. Some of these may be more relevant in animal models than in human disease. For example, some pathways that have been studied may be more involved in muscle development rather than a response to external stimuli, let alone the complex array of stimuli which may be present in COPD. In addition, there may be redundancy in the system so that multiple pathways have to be disrupted before skeletal muscle dysfunction arises. To date, few candidate …