title: Downregulation of the serum response factor/miR-1 axis in the quadriceps of patients with COPD.
abstract: BACKGROUND
  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.
authors: Section of Molecular Medicine, National Heart and Lung Institute, Imperial College London, SAF Building South Kensington Campus, London SW7 2AZ, UK.
authors: Amy
authors: A
authors: Lewis
authors: Joanna
authors: J
authors: Riddoch-Contreras
authors: Samantha A
authors: SA
authors: Natanek
authors: Anna
authors: A
authors: Donaldson
authors: William D-C
authors: WD
authors: Man
authors: John
authors: J
authors: Moxham
authors: Nicholas S
authors: NS
authors: Hopkinson
authors: Michael I
authors: MI
authors: Polkey
authors: Paul R
authors: PR
authors: Kemp
mesh_terms: D000368:Aged; D001706:Biopsy; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009135:Muscular Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D052097:Quadriceps Muscle / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C544547:MIRN1 microRNA, human; D035683:MicroRNAs; D026362:Serum Response Factor