Pathways associated with reduced quadriceps oxidative fibres and endurance in COPD

Reduced quadriceps endurance in COPD is associated with a predominance of type II glycolytic over type I oxidative fibres (fibre shift, FS) and reduced muscle energy stores. 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 FS. We measured lung function, physical activity, exercise performance, quadriceps strength and endurance (non-volitionally) in 38 GOLD Stage I-IV COPD patients and 23 healthy age-matched controls. Participants had a quadriceps biopsy; type I and II fibre proportions were determined using immunohistochemistry and FS defined using published reference ranges. Calcineurin A, phosphorylated adenosine monophosphate kinase-alpha (phospho-AMPK) and protein kinase A-alpha catalytic subunits were measured by western blotting and modulators of calcineurin activity, calmodulin, 14-3-3 proteins, and myocyte-enriched calcineurin-interacting protein-1 mRNA measured by western blotting and qPCR respectively. 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 than without FS. Phospho-AMPK levels correlated with quadriceps endurance in patients. Reduced phospho-AMPK may contribute to reduced quadriceps oxidative capacity and endurance in COPD.