Downregulation of the serum response factor/miR-1 axis in the quadriceps of patients with COPD. Issue 1 (13th October 2011)

• Record Type: Journal Article
• Authors: Lewis, Amy; Riddoch-Contreras, Joanna; Natanek, Samantha A; Donaldson, Anna; Man, William D-C; Moxham, John; Hopkinson, Nicholas S; Polkey, Michael I; Kemp, Paul R
• Is Part Of: Thorax. Volume 67:Issue 1(2012)
• Page Start: 26
• Page End: 34
• Publication Date: 2011-10-13
• Subjects: Muscle phenotype -- microRNA -- serum response factor -- COPD -- COPD mechanisms -- respiratory muscles -- sleep apnoea -- COPD exacerbations -- long term oxygen therapy (LTOT) -- lung physiology -- non invasive ventilation -- pulmonary rehabilitation -- allergic lung disease -- assisted ventilation -- asthma -- lung cancer -- non-small cell lung cancer -- sarcoidosis -- small cell lung cancer -- tuberculosis -- COPD pathology -- lung volume reduction surgery -- respiratory measurement -- exercise -- systemic disease and lungs; Chest -- Diseases -- Periodicals; Thorax; Chest -- Diseases; Periodicals; Periodicals; 617.54
• DOI: 10.1136/thoraxjnl-2011-200309
• Languages: English
• ISSNs: 0040-6376

Abstract

Abstract : Rationale: Muscle atrophy confers a poor prognosis in patients with chronic obstructive pulmonary disease (COPD), yet the molecular pathways responsible are poorly characterised. Muscle-specific microRNAs and serum response factor (SRF) are important regulators of muscle phenotype that contribute to a feedback system to regulate muscle gene expression. The role of these factors in the skeletal muscle dysfunction that accompanies COPD is unknown. Methods: 31 patients with COPD and 14 healthy age-matched controls underwent lung and quadriceps function assessments, measurement of daily activity and a percutaneous quadriceps muscle biopsy. The expression of muscle-specific microRNAs, myosin heavy chains and components of the serum response factor signalling pathway were determined by qPCR. Results: A reduction in expression of miR-1 (2.5-fold, p=0.01) and the myocardin-related transcription factors (MRTFs) A and B was observed in patients compared with controls (MRTF-A mRNA: twofold, p=0.028; MRTF-B mRNA: fourfold, p=0.011). miR-1 expression was associated with smoking history, lung function, fat-free mass index, 6 min walk distance and percentage of type 1 fibres. miR-133 and miR-206 were negatively correlated with daily physical activity. Insulin-like growth factor 1 mRNA was increased in the patients and miR-1 was negatively correlated with phosphorylation of the kinase Akt. Furthermore, the protein levels of histone deacetylase 4, another miR-1 target, were increased in the patients. Conclusions: Downregulation of the activity of the MRTF-SRF axis and the expression of muscle-specific microRNAs, particularly miR-1, may contribute to COPD-associated skeletal muscle dysfunction.