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Thorax 67:26-34 doi:10.1136/thoraxjnl-2011-200309
  • Chronic obstructive pulmonary disease
  • Original article

Downregulation of the serum response factor/miR-1 axis in the quadriceps of patients with COPD

Open Access
  1. Paul R Kemp1
  1. 1Section of Molecular Medicine, National Heart and Lung Institute, Imperial College London, London, UK
  2. 2NIHR Respiratory Biomedical Research Unit at the Royal Brompton, Harefield Foundation NHS Trust, Imperial College, London, UK
  3. 3Department of Asthma, Allergy and Lung Biology, King's College London School of Medicine, Kings Health Partners, London, UK
  1. Correspondence to Dr Paul R Kemp, Section of Molecular Medicine, National Heart and Lung Institute, Imperial College London, SAF Building South Kensington Campus, London SW7 2AZ, UK; p.kemp{at}imperial.ac.uk
  1. Contributors AL, JR-C, SAN, PRK, AD, MIP: experimental design, data collection and analysis. AL, SAN, PRK, MIP: analysis and interpretation of data. All authors made an important intellectual contribution to the manuscript drafting and editing.

  • Received 6 April 2011
  • Accepted 15 September 2011
  • Published Online First 13 October 2011

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.

Footnotes

  • MIP and PRK contributed equally to the study.

  • Funding This work was funded by the BBSRC, Wellcome Trust and the National Institute for Health Research (NIHR) Respiratory Biomedical Unit at the Royal Brompton Hospital and Imperial College. AL is a BBSRC PhD student, SAN received a Wellcome Trust Fellowship, AD received a NIHR Respiratory Biomedical Unit fellowship and WM is a NIHR Clinician Scientist. NSH is a HEFCE Clinical Senior Lecturer. MIP's salary is part funded by the NIHR Respiratory Biomedical Unit at the Royal Brompton Hospital and National Heart & Lung Institute.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by Royal Brompton and Harefield NHS Trust research ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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