Role of exosomal microRNA in driving skeletal muscle wasting in COPD

Skeletal muscle wasting is a key systemic complication of COPD influencing exercise capacity and mortality. Exosomes are nanosized vesicles of endosomal origin, which act as intercellular signalling organelles by transporting microRNA (miRNA) that alter gene expression in receiving cells. We investigated the differential expression of miRNAs in bronchoalveolar lavage fluid (BALF) and serum, with the aim of studying the effects of these identified miRNAs on skeletal muscle. Exosomes were isolated from matched serum and BALF from healthy controls (n=4) and mild to moderate COPD patients (n=4). Exosomal miRNA were identified using microarrays and validated with quantitative RT-PCR. Results were analysed using univariate statistical analysis. We identified 1 significantly up-regulated miRNA in COPD serum (p=0.01) and 4 significantly down-regulated in COPD BALF (p=0.03). Using in-silico analysis, we investigated the effects of these dysregulated miRNA on gene expression. This identified target genes involved in the mTORC1 signalling pathway, including gene S6K, a key regulator of skeletal muscle wasting. We successfully transfected ∼80% of cultured human skeletal muscle cells with the up-regulated miRNA and measured downstream gene expression. After 24 h we observed a 40,000-fold increase in the expression of this serum miRNA. At the same time, we identified a 52% reduction in S6K gene expression. We have identified differentially expressed miRNAs in the serum and BALF of COPD patients. This study demonstrates a novel role for exosomal miRNA, which potentially drives skeletal muscle wasting in patients with COPD.