Irisin is associated with clinical outcomes and up-regulated by long-acting anticholinergics in COPD

Abstract

Irisin is a myokine suggested to regulate energy expenditure and exercise capacity. It is regulated by peroxisome proliferator-activated receptor-γ coactivator-1-α (PGC1-a) and is proteolytically cleaved from fibronectin-type-III domain-containing protein-5 (FNDC5). The aim of our study was to investigate whether circulating irisin is associated with clinically relevant outcomes in COPD. Irisin was assessed in serum of 506 patients with COPD, GOLD grades II-IV at stable state and at exacerbation. The effect of inhaled long-acting muscarinic antagonists (LAMA) on serum irisin levels was subsequently evaluated in a proof-of-concept cohort of 40 COPD patients and confirmed in vitro using skeletal muscle cells (SkMC) by measuring irisin secretion by ELISA and gene expression of FNDC5 and PGC1-α by real time PCR. Serum irisin was increased at exacerbation as compared with stable state. At stable state, irisin was inversely associated with age-adjusted Charlson score and positively associated with 6MWD and LAMA treatment. Multivariate analysis revealed that the association of irisin with LAMA treatment remains significant after adjustment for age-adjusted score and 6MWD. A single inhalation of LAMA stimulated irisin levels after 4 hours. In SkMC, LAMA but not LABA or ICS, stimulated dose-dependently, irisin secretion. LAMA did not affect protein or gene expression of FNDC5 and PGC-1α, indicating an effect rather on irisin cleavage from FNDC5, than on de novo synthesis of irisin. These findings imply that long-acting anticholinergics increase circulating irisin, thus explaining some of the beneficial extra-pulmonary effects of these drugs in COPD.