Unbiased analysis of skeletal muscle molecular responses upon pulmonary rehabilitation in advanced COPD

Background: Pulmonary rehabilitation (PR) is a cornerstone in the management of COPD, targeting skeletal muscle to improve exercise performance. However, there is substantial inter-individual variability in the effect of PR on exercise performance, which cannot be fully accounted for by generic phenotypic factors. To identify groups with a differential response, we performed an unbiased integrative analysis of the skeletal muscle molecular responses to PR in COPD patients. Methods:M. Quadriceps biopsies were obtained from 51 COPD patients (FEV1 %pred., 34 (26–41)) before and after 4 weeks of in-patient PR. Exercise performance was assessed by incremental cycle ergometry. Skeletal muscle molecular markers were grouped by network-constrained clustering, and their expression values — assessed by qPCR and Western blot — were reduced to process scores by principal component analysis. Patients were subsequently clustered based on their process scores. Results: Two clusters differed in PR-induced Autophagy, Myogenesis, Glucocorticoid signalling, and Oxidative metabolism regulation. Specifically, mRNA expression of e.g. ULK1, BECN1, LC3B, MYOD1, CDH15, NFKBIA, TRIM54, FBXO30, FBXO21, FIS1, MFN1, PARK2, PPARGC1A, PPARGC1B, COX4I1, and MHC2 decreased in cluster 0, whereas they were unaltered or increased non-significantly in cluster 1. Clusters did not differ in general characteristics, but a higher percentage of patients in cluster 0 exceeded MCID in peak work load upon PR (61 vs 21%, P=0.02). Conclusion: Cluster analysis identified two patient groups with distinct skeletal muscle molecular responses to rehabilitation, characterized by differences in functional improvements upon PR.