Distinct skeletal muscle molecular responses to pulmonary rehabilitation in chronic obstructive pulmonary disease: a cluster analysis

Abstract

Background Pulmonary rehabilitation (PR) is a cornerstone in the management of chronic obstructive pulmonary disease (COPD), targeting skeletal muscle to improve functional performance. However, there is substantial inter‐individual variability in the effect of PR on functional performance, which cannot be fully accounted for by generic phenotypic factors. We performed an unbiased integrative analysis of the skeletal muscle molecular responses to PR in COPD patients and comprehensively characterized their baseline pulmonary and physical function, body composition, blood profile, comorbidities, and medication use. Methods Musculus vastus lateralis biopsies were obtained from 51 COPD patients (age 64 ± 1 years, sex 73% men, FEV 1 , 34 (26–41) %pred.) before and after 4 weeks high‐intensity supervised in‐patient PR. Muscle molecular markers were grouped by network‐constrained clustering, and their relative changes in expression values—assessed by qPCR and western blot—were reduced to process scores by principal component analysis. Patients were subsequently clustered based on these process scores. Pre‐PR and post‐PR functional performance was assessed by incremental cycle ergometry and 6 min walking test (6MWT). Results Eight molecular processes were discerned by network‐constrained hierarchical clustering of the skeletal muscle molecular rehabilitation responses. Based on the resulting process scores, four clusters of patients were identified by hierarchical cluster analysis. Two major patient clusters differed in PR‐induced autophagy ( P < 0.001), myogenesis ( P = 0.014), glucocorticoid signalling ( P < 0.001), and oxidative metabolism regulation ( P < 0.001), with Cluster 1 (C1; n = 29) overall displaying a more pronounced change in marker expression than Cluster 2 (C2; n = 16). General baseline characteristics did not differ between clusters. Following PR, both 6 min walking distance (+26.5 ± 8.3 m, P = 0.003) and peak load on the cycle ergometer test (+9.7 ± 1.9 W, P < 0.001) were improved. However, the functional improvement was more pronounced in C1, as a higher percentage of patients exceeded the minimal clinically important difference in peak workload (61 vs. 21%, P = 0.022) and both peak workload and 6 min walking test (52 vs. 8%, P = 0.008) upon PR. Conclusions We identified patient groups with distinct skeletal muscle molecular responses to rehabilitation, associated with differences in functional improvements upon PR.

Relationship between pulmonary function and physical performance among community‐living people: results from Look‐up 7+ study

“…23 A number of studies have assessed the relationships of respiratory function with muscle mass and muscle function in patients with chronic obstructive pulmonary disease (COPD). [24][25][26] These previous studies were conducted in older patients in hospitals and/or nursing homes, not in community-dwelling subjects, and had mostly small sample sizes. Nevertheless, few studies have explored lung function in healthy subjects.…”

Dysregulated myogenesis and autophagy in genetically induced pulmonary emphysema

“…We report here that myogenic capacity and satellite cells replication are both reduced in an animal model of COPD. Although relatively unexplored in non-primarily muscle diseases, myogenesis is emerging as an important mechanism regulating muscle integrity in COPD and other pulmonary diseases [18,[21][22][23][24][25][26][27]. Following an injurious event, satellite cells undergo an initial phase of symmetrical replication giving rise to similar daughter cells which expand the pool of myogenic cells [62].…”

“…Indeed, the frequency and severity of COPD exacerbations and infections powerfully associate with loss of muscle and lung integrity, and with higher mortality over time [13][14][15][16]. While strong evidence indicates that dysfunctional myogenesis contributes to muscle loss in non-primarily muscular conditions such as aging and cancer [17][18][19][20], recent clinical observations also suggest its role in COPD [18,[21][22][23][24][25][26][27]. Moreover, accumulating evidence indicates that biological signals that are prevalent in COPD patients such as hypoxia, hypercapnia and smoking regulate muscle response to injury as well [28][29][30].…”

Locomotor Muscles in COPD: The Rationale for Rehabilitative Exercise Training

“…Combined endurance (performed at the ventilatory threshold or 60% WR peak ) and resistance training had a non-significant increase in the activation of Akt/mTOR pathway in normoxemic, but not in hypoxemic, patients (Costes et al, 2015). Actually, greater beneficial changes in muscle molecular responses to rehabilitative exercise training were recently associated with larger gains in exercise capacity in COPD (Kneppers et al, 2019). Overall, the fact that cachectic and hypoxemic patients with COPD showed different response to training than their respective non-cachectic and normoxic counterparts, specific management in the frailer patients might be necessary to trigger induce positive muscle adaptations [e.g., nutritional ergogenic aids (Fuld et al, 2005;Villaca et al, 2006) or blockade of negative muscle regulators (Polkey et al, 2019) in selected patients].…”