Circulating microRNA in Chronic Obstructive Pulmonary Disease

Abstract

Skeletal muscle dysfunction in COPD is associated with increased morbidity. Novel agents might reverse skeletal muscle dysfunction through different mechanisms since the biopsy picture in COPD patients is heterogenous. Thus there is a need for a biomarker of skeletal muscle dysfunction which could both be measured in blood and obviate the need for a biopsy. Previous work has found that muscle-specific microRNA (miR-1, miR-499, miR-206 and miR-133) are down-regulated in the quadriceps of COPD patients. Tissue specific miRNA circulate in the blood at detectable levels and are currently under investigation as biomarkers of other diseases. I therefore hypothesised that muscle-specific microRNA might be clinically viable biomarkers of skeletal muscle dysfunction. The studies in this thesis found that: 1. Levels of circulating muscle-specific microRNA (miR-1, miR-133, miR-206 and miR-499) were increased in stable COPD patients. The increase in muscle-specific microRNA in the stable COPD patients suggests that continual muscle turnover occurs outside of times of disease exacerbation. 2. Plasma levels of muscle-specific miRNA were not different in COPD patients admitted to hospital for an exacerbation of their disease compared to stable COPD patients. 3. Most muscle-specific microRNA did not change in muscle with acute exercise. I demonstrated an increase in miR-181 (an miRNA not restricted to, but with known function in muscle) one hour after acute exercise in the quadriceps muscle of COPD patients. However when fold change was calculated for the COPD patients and controls, there was no statistical difference found. There were no detectable miR-181 changes measured in blood. 4. Finally, I used a microarray approach to investigate other circulating microRNA that might to be useful to separate patients based on their lean muscle-mass. COPD patients with a reduced skeletal muscle mass had a reduced number of microRNA associated with growth and cell pluripotency, further studies are required to validate these findings. Taken together, the results from this thesis suggest that the microRNA analysed were detectable in blood, but they could not be usefully used (based on current analysis) as biomarkers of quadriceps dysfunction.