title: Pathways associated with reduced quadriceps oxidative fibres and endurance in COPD.
abstract: Reduced quadriceps endurance in chronic obstructive pulmonary disease (COPD) is associated with a predominance of type II glycolytic fibres over type I oxidative fibres (fibre shift) and reduced muscle energy stores. The molecular mechanisms responsible for this remain unknown. We hypothesised that expression of known regulators of type I fibres and energy production in quadriceps muscle would differ in COPD patients with and without fibre shift. We measured lung function, physical activity, exercise performance, quadriceps strength and endurance (nonvolitionally) in 38 Global Initiative for Chronic Obstructive Lung Disease stage I-IV COPD patients and 23 healthy age-matched controls. Participants underwent a quadriceps biopsy: type I and II fibre proportions were determined using immunohistochemistry and fibre shift defined using published reference ranges. Calcineurin A, phosphorylated AMP kinase (phospho-AMPK)-α, protein kinase A-α catalytic subunits, modulators of calcineurin activity and calmodulin, 14-3-3 proteins were measured by Western blotting, and myocyte-enriched calcineurin-interacting protein-1 mRNA measured by quantitative PCR. Downstream, nuclear myocyte enhancer factor-2 capable of DNA binding was quantified by transcription factor ELISA. Unexpectedly, calcineurin expression was higher, while phospho-AMPK was lower, in COPD patients with fibre shift compared to COPD patients without fibre shift. Phospho-AMPK levels correlated with quadriceps endurance in patients. Reduced phospho-AMPK may contribute to reduced quadriceps oxidative capacity and endurance in COPD.
authors.affiliation: Dept of Respiratory Medicine, National Institute for Health Research Respiratory Biomedical Research Unit of Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Institute, Imperial College London, London, UK. a.natanek@imperial.ac.uk
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Natanek
authors.forename: Harry R
authors.initials: HR
authors.lastname: Gosker
authors.forename: Ilse G M
authors.initials: IG
authors.lastname: Slot
authors.forename: Gemma S
authors.initials: GS
authors.lastname: Marsh
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Hopkinson
authors.forename: John
authors.initials: J
authors.lastname: Moxham
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kemp
authors.forename: Annemie M W J
authors.initials: AM
authors.lastname: Schols
authors.forename: Michael I
authors.initials: MI
authors.lastname: Polkey
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000368:Aged; D019703:Calcineurin / Q000378:metabolism; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D064326:MEF2 Transcription Factors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation; D010807:Physical Endurance; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D052097:Quadriceps Muscle / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D012129:Respiratory Function Tests; D013147:Spirometry
chemical_list: D048948:14-3-3 Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D012333:RNA, Messenger; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D019703:Calcineurin; D010100:Oxygen