Impact of ACE inhibition on mechanisms of skeletal muscle wasting in COPD

Chronic obstructive pulmonary disease (COPD) is a major public health problem in the UK and worldwide. As well as being a lung disease COPD has well-recognised and important consequences for other parts of the body, and these contribute to the enormous burden of disability associated with the condition. Muscle weakness is one of these consequences, and is associated with reduced exercise capacity, reduced quality of life and increased mortality. Since efforts to treat the lung disease have to date had limited impact it is important to address the systemic complications of the disease directly. The molecular pathways involved in muscle wasting are gradually becoming understood. An important signalling pathway in muscle links the hormone insulin-like growth factor with the production of ?atrogenes? which are substances that mark muscle proteins for breakdown. There is evidence in animal models that this could be influenced by drugs called angiotensin converting enzyme inhibitors (ACE-I). This class of drugs are widely used for the treatment of high blood pressure and heart failure, and in fact patients prescribed these drugs for that reason have better preservation of limb muscle than those who receive another class of drug.
We propose testing this possibility in humans by performing a placebo controlled study of an ACE inhibitor in 70 patients with COPD who have weak quadriceps (one of the main leg muscles). We will measure quadriceps muscle endurance using a repetitive magnetic stimulator before treatment and then after two months on either treatment or placebo. A small sample of muscle will be taken before and after treatment to allow u to study the molecular mechanisms involved.
We hypothesise that ACE inhibitors will cause a reduction in atrogene levels and that this will occur in tandem with an increase in quadriceps strength and endurance. If this is the case it would open the way for a much larger study to see if use of ACE inhibitors could improve exercise capacity and quality of life in people with COPD.

Chronic obstructive pulmonary disease (COPD) is projected to become the fifth biggest cause of disability adjusted life years by 2020. Although it is primarily a lung disease it has important systemic complications. Skeletal muscle weakness is one of these but the mechanisms involved in muscle loss are incompletely understood.
A key catabolic pathway involved in skeletal muscle atrophy is mediated through expression of two muscle-specific ubiquitin ligases, the atrogenes, atrogin-1 and MuRF-1, which are themselves dependent on the activity of FoxO transcription factors. In health these transcription factors are rendered inactive by phosphorylation by AKT. IGF-1 and insulin act through the PI3K/AKT pathway to disable FoxO transcription factors, prevent expression of atrogenes and thus act in an anticatabolic way. There is evidence that there is increased expression of both atrogin-1 and MuRF-1 in skeletal muscle in patients with COPD. Animal studies suggest that angiotensin II may cause muscle wasting via this pathway.
We therefore wish to test the hypothesis that ACE inhibition will have a beneficial effect on the IGF-1/AKT/FOXO/atrogene pathway of muscle wasting in patients with COPD and that this will be associated with improvements in skeletal muscle function. Skeletal muscle function will be assessed using a novel, non-volitional measure of endurance developed in our laboratory.
We propose a randomised double blind study of ACE inhibition in 70 patients with COPD who have established quadriceps weakness. Patients will have their quadriceps endurance assessed using repetitive magnetic stimulation, a non-volitional technique that we have developed and a muscle biopsy performed to allow us to study the pathways involved. These measures will be repeated after two months and the two groups compared.