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Muscle Changes due to exercise in COPD and healthy individuals
ISRCTN ISRCTN10906292
DOI 10.1186/ISRCTN10906292
ClinicalTrials.gov identifier
EudraCT number
Public title Muscle Changes due to exercise in COPD and healthy individuals
Scientific title Mitochondrial adaptations to Aerobic Training in COPD and Health: the MATCH study
Acronym MATCH Study
Serial number at source 14080
Study hypothesis Chronic Obstructive Pulmonary Disease (COPD) is a major cause of illness and disability. Patients are breathless and have limited exercise capacity.

Interventions targeting the skeletal muscles may be of therapeutic benefit, as demonstrated by the unequivocal benefits of exercise training in the context of pulmonary rehabilitation.

The mitochondria perform a vital function for oxidative energy metabolism within cells. They are responsible for the aerobic energy production in muscle cells which is essential for prolonged exercise. A major contributor to the exercise limitation experienced by COPD patients is recognised to be a reduction in oxidative capacity at the level of the skeletal muscle mediated by reduced mitochondrial density and function.

Mitochondrial density and function are potential therapeutic targets in COPD, however it remains uncertain whether impaired mitochondrial density and/or function are attributable to ageing, inactivity and deconditioning, a COPD specific “mitochondropathy” or a combination of these factors. This study will assess:

1. Mitochondrial quality, density and function in COPD patients compared to both age-matched, and young healthy control (HC) volunteers.
2. The impact of aerobic (endurance) training on whole-body oxygen consumption, muscle gene expression and mitochondrial density and function in COPD patients and young and old healthy controls and the time-course of any changes observed.
3. The impact of detraining on these same parameters following exercise training. This is an important facet of the study as it is known that in healthy, young volunteers the decline in mitochondrial function with detraining is more rapid than the decline in maximal oxygen consumption. It is pertinent therefore to know whether this is exacerbated in COPD particularly given they are likely to be more inactive during detraining.

Importantly the approach proposed will enable us to differentiate the effect of ageing from any COPD specific effects.

More details can be found at: http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=14080
Lay summary Background and study aims
Chronic obstructive pulmonary disease (COPD) is predominantly a lung disease that is irreversible. Interestingly we have found that patients with this condition are not only short of breath, but also struggle with activities of daily living (walking, housework, climbing stairs etc) that seems not to be related to the lung damage. This has been an area of growing interest.
We have found that in COPD patients, muscle functions (predominantly in the legs) are abnormal when compared to ‘healthy’ individuals. This is seen as a possible target of therapy, both in terms of providing focussed exercise and also possible drug therapy.

Who can participate?
COPD patients:
Target of 20 patients to complete the trial
60-80 years of age
COPD diagnosis
Not on long term anti-coagulants (e.g. Warafrin)
Not Diabetic
Ex-smoker (>1year)
Not done Pulmonary rehabilitation in the preceding year

Healthy patients:
Aiming for 10 patients in each age group (i.e. 20 in total) to complete the study.
Sedentary individuals (not doing more than 30 minutes of exercise three times a day)
Ages 18-30 or 60-80
Not Diabetic


What does the study involve?
The study essentially involves 8 weeks of training; 3 times a week of cycling. This is then followed by 4 weeks of ‘de-training’ where there is no exercise.
Patients will have 5 muscle biopsies at different time points of the study, where we will be performing numerous specialist tests on muscle function. We will also be looking at other measures such as exercise capacity, muscle strength and mass, and these will be at 4-5 time points throughout the study.

What are the possible benefits and risks of participating?
We would expect you to benefit from improvements in your fitness as a result of the exercise programme, although this may not occur in all participants. We hope the information we get from this study will be helpful in understanding the problem of muscle dysfunction in patients with COPD and help develop treatments for this problem.
The risks are minimal. The muscle biopsies are low risk and will be done by an experienced clinician, it is done under local anaesthetic, and people can carry on with normal activities straight away with minimal discomfort. You may be left with a small scar at the end.

Where is the study run from?
The study will be involved at the Leicester Glenfield Hospital and Nottingham University, at the Queens Medical Centre. We shall be recruiting from Nottingham and Leicester.

When is the study starting and how long is it expected to run for?
Recruitment is predicted to start Mid/Late May 2013. The Trial will end on Jan 2015.

Who is funding the study?
The funding is provided by the MRC (medical research council).

Who is the main contact?
Dr Bhavesh Popat
bhavesh.popat@uhl-tr.nhs.uk
Ethics approval NRES Committee West Midlands - Coventry & Warwickshire, ref number: 13/WM/0075
Study design Non-randomised interventional and observational case-controlled study
Countries of recruitment United Kingdom
Disease/condition/study domain Chronic Obstructive Pulmonary Disease / Respiratory
Participants - inclusion criteria COPD Subjects:
1. Clinically stable patients (no exacerbation within last 4 weeks)
2. Aged 60-80
3. Spirometric criteria for COPD (FEV1/FVC < 0.7, FEV1 < 80% predicted) with significant exercise limitation (MRC breathlessness score 3 or worse) and
4. Clinical picture of COPD.

Healthy Control Subjects:
1. Age matched (60 – 80years) and young (18- 30 years) healthy controls will be recruited from the local population.
2. Spirometric criteria (FEV1/FVC >0.7, FEV1 >80%).
3. Target Gender: Male & Female; upper age limit 80 years ; lower age limit 18 years
Participants - exclusion criteria COPD Subjects:
1. Subject on any of the following:
1.1. Long-term oral corticosteroids
1.2. Anticoagulation (e.g. warfarin)
1.3. Long term oxygen therapy
2. Co-morbid conditions preventing exercise training or causing exercise limitation or intramuscular inflammation including type II diabetes.
3. Undergone pulmonary rehabilitation in the preceding year (as there may be residual benefits)
4. Current smokers will be excluded as cigarette smoke may have a direct affect on mitochondrial function independent of disease state. To exclude the possibility of residual effects of smoking, all participants must report no smoking habit for 1 year prior to entry into the study.

Healthy Control Subjects:
1. Any inflammatory illnesses (e.g. type II diabetes, inflammatory bowel disease).
2. Any condition causing exercise limitation.
3. Engaged in regular physical activity or exercise regime
4. As for COPD patients, healthy volunteers must not have smoked in the 1 year preceding entry into the study
Anticipated start date 07/05/2013
Anticipated end date 01/01/2015
Status of trial Ongoing
Patient information material Not available in web format, please use the contact details below to request a patient information sheet
Target number of participants UK Sample Size: 56; Description: Aim is for 20 COPD patients, compared to 20 controls (10 age matched healthies and 10 young healthy participants). Total number of 56 participants
Interventions Exercise Training, We shall be undertaking aerobic exercising training on our patients, which will involve 24 training sessions over a 12 week period.
Primary outcome measure(s) Primary end points for outcome will be measured at:- baseline, 1-week post baseline, 4- weeks post exercise, 8 weeks post exercise (end of exercise), and post detraining (4 weeks) for muscle biopsies
1. These will be the tests we shall be measuring from the biopsies:- Mitochondrial DNA and deletions to provide a measure of mitochondrial quality (baseline biopsy only).
2. Maximal rates of mitochondrial ATP production (using a variety of mitochondrial substrates) utilising a high-sensitivity firefly-luciferase method for determining mitochondrial ATP production capacity that is known to be highly sensitive to defects in mitochondrial function in human endotoxaemia and improvements in mitochondrial function with exercise training.
3. Mitochondrial enzyme maximal activities (pyruvate dehydrogenase complex, TCA cycle and electron transport chain) to give an index of mitochondrial density. In addition, cytosolic enzyme activities will be determined to assess relative changes in non-mitochondrial energy production capacity.
4. We will conduct a broad investigation of muscle mRNA expression using low density array (LDA) cards. Specifically, we will utilise automated 384 well cards to assess targeted gene expression covering a wide range of gene families associated with inflammation, apoptosis, cell cycle/growth/differentiation, mitochondria, RNA processing, DNA replication and repair, immune responses, the NFkB pathway, the ubiquitin proteasome pathway and other metabolic processes.
5. Guided by the outcome of the gene expression measurements, targeted proteins will also be measured by Western blotting (including mitochondrial linked targets e.g., PPARs, PGC1α, AMPK).
6. Muscle fibre composition using silver staining (to control for training induced increases in slow muscle fibre area).
Secondary outcome measure(s) 1. Muscle Strength testing
2. Maximal VO2
3. Body composition (Fat Free mass)
Sources of funding 1. Medical Research Council (MRC) (UK) Grant Codes: G1001362/1
2. NIHR Leicester Respiratory Biomedical Research Unit (UK)
Trial website
Publications
Contact name Dr  Bhavesh  Popat
  Address Clinical Research Fellow
Leicester Respiratory BRU
Glenfield Hospital
Groby Road
  City/town Leicester
  Zip/Postcode LE3 9QP
  Country United Kingdom
  Email bhavesh.popat@uhl-tr.nhs.uk
Sponsor University Hospitals of Leicester NHS Trust (UK)
  Address Leicestershire, Northamptonshire & Rutland
Trust Headquarters
George Hine House
Gipsy Lane
  City/town Leicester
  Zip/Postcode LE5 0TD
  Country United Kingdom
  Sponsor website: http://www.leicestershospitals.nhs.uk/
Date applied 25/04/2013
Last edited 03/05/2013
Date ISRCTN assigned 26/04/2013
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