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

Lead Research Organisation: University Hospitals of Leicester NHS
Department Name: Respiratory Medicine

Abstract

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.

Technical Summary

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.
 
Description ATS/ARS statement on skeletal muscle dysfunction in COPD
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description ERS taskforce on Nutrition in COPD
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description National Clinical COPD audit
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Pulmonary Rehabilitation Quality Standards
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact I co-chair the British Thoracic Society Quality Standards Committee with responsibility for drafting and agreeing the publication of the standards. These standards will provide guidance for commissioners and providers on improving quality in pulmonary rehabilitation provision
 
Description COPD MAP (extension award), Workpackage 4
Amount £856,574 (GBP)
Funding ID G1001362/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2012 
End 09/2015
 
Description MRC COPD MAP G1001362
Amount £426,854 (GBP)
Funding ID G1001362 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2011 
End 06/2012
 
Description Novartis research collaboration
Amount £200,000 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 12/2012 
End 07/2015
 
Title Antibody development 
Description Optimisation of antibodies for protein determinations in human muscle. 
Type Of Material Antibody 
Year Produced 2009 
Provided To Others? Yes  
Impact Too early 
 
Title Ultrasound assessment of quadriceps muscle mass 
Description We have developed and investigated the performance of bedside ultrasound to assess quadriceps muscle mass in patients with COPD over time and in response to resistance training. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2009 
Provided To Others? Yes  
Impact Incorporation of this measurement in NIHR CLAHRC research programmes within our group 
 
Title Advanced COPD cohort 
Description Establishment of a clinical cohort of patients with advanced COPD supported by a bespoke database. Research support provided by the Leicester Respiratory BRU 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Integration of structured data collection within a specialist clinical service 
 
Description MRC/ARUK Centre for Musculoskeletal Ageing 
Organisation Glenfield Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We are investigating the hypothesis that mitochondrial dysfunction in COPD and healthy elderly volunteers is attributable to inactivity rather than COPD pathology and ageing per se.
Collaborator Contribution Staffing of post-doc to undertake wet lab analyses
Impact N/A at this time
Start Year 2013
 
Description Press Release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact University Press release.

Picked up by the BBC for wider dissemination. This resulted in members of the general public contacting me about our MRC research project.
Year(s) Of Engagement Activity 2007
 
Description Roundhill Primary School, Beeston, Nottingham 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 2 x 0.5 day primary school class of lung function (and how exercise can have positive effects in COPD).

Children got an appreciation of lung function and that lung disease greatly affects other body systems and in particular skeletal muscles.
Year(s) Of Engagement Activity 2008