Is the Anaerobic Quadriceps Muscle Phenotype in Chronic Obstructive Pulmonary Disease Mediated by Reduced Muscle Concentrations of Peroxisome Proliferator-Activated Receptors Alpha and Delta?

There has been considerable interest in finding methods of improving quadriceps function in COPD, since quadriceps dysfunction is associated with reduced exercise capacity5 and survival in patients16, independently of lung function. Pulmonary rehabilitation (PR) courses comprising exercise and education can increase oxidative enzymes, strength and endurance of the quadriceps in patients with COPD17 and improve walking capacity even over a period of 8 weeks12, 18. However, PR is not a complete solution: not all regions of the UK offer PR, PR only has on average a 50% uptake rate by patients and the drop-out rate is 30%. Also a significant proportion of patients (about 30%) do not increase their exercise capacity as a result of PR19, perhaps because breathlessness limits the training they complete or their peripheral muscle strength is normal19. Therefore, there is interest in alternative treatments or add-ons to exercise, particularly in terms of localised muscle treatments that are not limited by impaired respiratory function. Repetitive electrical stimulation of the femoral nerve (rES) appears to be an effective alternative method of passively training the quadriceps muscle. 30 minutes rES at 10Hz five times a week to both legs increased muscle strength and exercise performance in patients with COPD21 and those with heart failure22. Similar results have been achieved with fifteen minutes of repetitive magnetic stimulation of the femoral nerve (rMS) three times a week23. However, treatment studies with rES to investigate effects on exercise performance have often used separate treatment and control groups which introduces inter-subject differences into studies already limited by sample size243 and have only used voluntary measures of quadriceps function96. The only biopsy study of rES used a cross-over design but biopsies were only taken before and after the rES training period and not before and after the control period.244 The rMS study involved a total of eighteen subjects (ten assigned to rMS, eight to control) and biopsies were not taken to evaluate histological changes in the muscle. With this study, I sought primarily to evaluate the changes in quadriceps fibre characteristics as a result of an intensive rMS protocol, and secondarily, compare changes in quadriceps function as the result of rMS with the clinical gold standard for improving muscle function, PR.

Methods

Ethical approval The Research Ethics Committee of the Ealing & West London Mental Health Trust approved the study (06/Q0410/54). The trial was registered with National Clinical Trials Database (NCT 00737698). 2.13.1

Sample size calculation The sample size required for the training study was based on power calculations from a previous study on PR from our group221 and pilot data from our group on the effect of rMS on muscle strength (Swallow et al, unpublished) using Stata 10 statistical software. The power calculations were based on functional improvements (increase of 54m on 6MW as a result of PR and 10% increase in quadriceps TwQ as a result of rMS, as the minimum clinically significant increments) rather than increases in muscle fibre CSA or type I fibre proportions as the data for the latter was not available. We chose an increase of 10% twitch force as the minimally significant increment as previous data from Mador et al showed a 9.7% increase in twitch force as the result of 8 weeks PR17. A conventional power of 80% with a two-tailed p value of ≤0.05 was chosen indicating that a minimum of ten patients were required for the PR arm and twenty six for the rMS arm. We aimed to recruit fifteen to the PR group and thirty to the rMS group to allow for patient drop-out at the rates we have previously encountered. At completion, there were seventeen in the PR group and thirty seven in the rMS group.

Subject selection Eighty six COPD patients consented for the cross-sectional study also consented for the training study therefore the inclusion and exclusion criteria were as for the cross-sectional study. Patients were precluded from starting any new exercise regimen or new regular medication from consent to completion of the study, and patients were encouraged to contact me on day 1 of an acute exacerbation so appropriate treatment could be instituted. The study design and flow of participants through the study are shown in Fig. 4.1 and 4.2.