Molecular Approaches to Reversing Muscle Wasting in COPD. The Role of Resistance Training and Protein Supplementation

Chronic diseases are a major challenge for human health in the 21st century. The UK and worldwide burden of chronic disease is expected to increase in future years. Chronic Obstructive Pulmonary Disease (COPD) is an important chronic disease of the chest and is a leading cause of disability among older people. Muscle wasting and weakness is an important feature of COPD. Patients with muscle wasting are more disabled, have a poorer prognosis and require more healthcare resources. Loss of muscle bulk and function is important because it may be a treatable consequence of a condition in which the underlying lung disease is usually irreversible. The value of this approach is illustrated by the benefits of physical training, which have been clearly demonstrated in COPD. However, little is known about the causes of muscle wasting and weakness or the mechanisms by which physical training improves muscle function in COPD. We have recently identified genes involved in the regulation of muscle wasting and growth in healthy young and elderly humans and demonstrated that the functioning of these genes is profoundly affected by periods of immobility and exercise. Recent work has also demonstrated that dietary supplementation of protein enhances muscle growth during exercise training in healthy humans. We will extend these observations to study muscle wasting and growth in the clinical setting of COPD. We will study the functioning of genes recently identified as important in the regulation of muscle growth and wasting in patients with COPD compared with healthy volunteers of the same age. We will also study the effects of an eight-week lower limb strength-training programme on the functioning of these genes. This will help us understand how training works and how training affects the genes that regulate muscle growth. It may be beneficial to supplement individuals with additional dietary protein at the time of training. We will test this theory by randomly allocating patients in the study to receive a protein rich drink or a non-nutritive placebo after each bout of training. We will also measure muscle bulk and muscle function during the study. This research will provide new insights into the genetic mechanisms of muscle wasting and weakness and how the functioning of these genes can be influenced by interventions such as training and nutrition. This information will be a significant advance in the development of new treatments aimed at improving muscle function in chronic diseases such as COPD.

Chronic Obstructive Pulmonary Disease (COPD) is the most important cause of disability due to respiratory disease in the UK and worldwide. Skeletal muscle wasting is a common and clinically important feature of many chronic diseases and is an independent predictor of prognosis and disability in COPD. Muscle function and mass can be improved by appropriate physical training in COPD but the molecular mechanisms underlying alterations in muscle mass in COPD and the response to interventions such as training remain unknown. Recent work at the CISBM has provided new insights into the molecular regulation of muscle atrophy and re-growth during immobilisation and training in healthy humans. Furthermore, there is evidence in healthy humans that dietary protein supplementation augments the positive effects of resistance training on muscle mass. We plan to extend these observations in a collaborative project between the CISBM and the Pulmonary Rehabilitation Research Group at UHL to the important clinical setting of COPD. Our aim is to study the molecular regulation of muscle mass in COPD compared with healthy age matched volunteers and to determine the effects of resistance training with and without dietary protein supplementation on these mechanisms. These objectives will be achieved by conducting a parallel group study of lower limb resistance training in COPD patients and healthy age matched controls. We will measure the expression of genes and signalling pathways in quadriceps muscle biopsies obtained at baseline, during and at the end of training. These genes have previously been identified as associated with the regulation of muscle mass in vivo in humans. To study the effects of protein supplementation patients will be randomised to receive a dietary protein supplement or placebo after each training session. The training programme will comprise maximal isokinetic thigh muscle extensions performed three times weekly for eight weeks. Because gene expression is likely to be different in patients with and without muscle wasting patients will be stratified into wasted and non-wasted groups prior to training using baseline DEXA measurements. In addition we will measure muscle mass by DEXA and isokinetic muscle function during the study. Secondary outcomes will be whole body exercise performance and systemic inflammatory cytokine concentrations. The results of this research will provide insight into the mechanisms of muscle wasting in COPD and will be a significant advance in the development of new therapies targeted at skeletal muscle wasting in COPD and other chronic diseases.