Lung transcriptomics reveals the underlying mechanism by which aerobic training enhances pulmonary function in chronic obstructive pulmonary disease

Abstract

Background: Aerobic training is the primary method of rehabilitation for improving respiratory function in patients with chronic obstructive pulmonary disease (COPD) in remission. However, the mechanism underlying this improvement is not yet fully understood. The use of transcriptomics in rehabilitation medicine offers a promising strategy for uncovering the ways in which exercise training improves respiratory dysfunction in COPD patients. In this study, lung tissue was analyzed using transcriptomics to investigate the relationship between exercise and lung changes.

Methods: Mice were exposed to cigarette smoke for 24 weeks, followed by nine weeks of moderate-intensity treadmill exercise, with a control group for comparison. Pulmonary function and structure were assessed at the end of the intervention and RNA sequencing was performed on the lung tissue.

Results: Exercise training was found to improve airway resistance and lung ventilation indices in individuals exposed to cigarette smoke. However, the effect of this treatment on damaged alveoli was weak. The pair-to-pair comparison revealed numerous differentially expressed genes, that were closely linked to inflammation and metabolism.

Conclusions: Further research is necessary to confirm the cause-and-effect relationship between the identified biomarkers and the improvement in pulmonary function, as this was not examined in the present study.

Keywords: Chronic obstructive pulmonary disease; Exercise training; Pulmonary function; Rehabilitation; Transcriptomics.

Fig. 1

COPD mouse model establishment process and exercise intervention protocol. The mice were randomly divided into CG, MG and EG (n = 8). MG and EG were exposed to smoke for 24 weeks to replicate the COPD model, and the latter received 9 weeks of aerobic exercise intervention. Finally, multiple indicators in each group were examined. CG, control group; MG, model group; EG, exercise group. Values represented the means ± SD

Fig. 2

Exercise training improved the pulmonary function of COPD mice. Raw index (RI) (A), dynamic lung compliance (Cdyn) (B), peak inspiratory flow rate (PIF) (C), vital capacity (VC) (D), expiratory volume (ERV) (E), peak expiratory flow (PEF) (F), forced exhalation volume (FEV) in 50 microseconds (G), 100 microseconds (H) and forced vital capacity (FVC) (I) in three groups were showed orderly. Treadmill training decreased RI and increased PIF, VC, ERV, FEV50 and FVC in COPD mice. CG, control group; MG, model group; EG, exercise group. Values represented the means ± SD. ^*P < 0.05

Fig. 3

Effect of exercise training on lung structure in mice. The lung tissue structure of mice in blank group (A, bar = 500 μm; B, bar = 100 μm), model group (C, bar = 500 μm; D, bar = 100 μm) and exercise group (E, bar = 500 μm; F, bar = 100 μm) was observed, and the alveolar cross-sectional area of mice were compared in three randomly selected fields (G). The lung structures of MG and EG mice exhibited typical emphysema, compared to healthy mice. After exercise intervention, the alveolar size of EG mice did not show significant changes. CG, control group; MG, model group; EG, exercise group; CSA, cross-sectional area. Values represented the means ± SD. ^*P < 0.05

Fig. 4

Venn diagrams of DEGs were identified in different comparisons, including (A) upregulated DEGs and (B) downregulated DEGs. The venn diagrams revealed overlapping DEGs in the comparisons between groups, including three upregulated DEGs and one downregulated DEGs in the three comparisons. CG, control group; MG, model group; EG, exercise group

Fig. 5

Correlation of DEGs among three different groups (A) and hierarchical clustering analysis of DEGs (B) in the lung tissues were conducted in the subsequent analysis. Volcano maps and heat maps revealed the significance of DEGs expression, and those DEGs with more significant differences in expression will be focused on. CG, control group; MG, model group; EG, exercise group

Fig. 6

Molecular function of differentially expressed genes. (A) GO analysis of downregulated DEGs; (B) GO analysis of upregulated DEGs. The above results helped to understand the common characteristics of the molecular functions of the selected DEGs. According to the GeneRatio, those functions with more enriched DEGs and smaller P-values will be concerned. CG, control group; MG, model group; EG, exercise group

Fig. 7

KEGG pathway analysis of DEGs. (A) KEGG pathway analysis of downregulated DEGs; (B) KEGG pathway analysis of upregulated DEGs. Signaling pathways with high enrichment score will be considered as potential mechanisms by which exercise improves respiratory function in COPD. CG, control group; MG, model group; EG, exercise group

Fig. 8

The potential pathways of exercise training to improve pulmonary function. Aerobic exercise may improve COPD respiratory dysfunction by regulating the body’s inflammatory response and metabolism. Multiple pathways, including MAPK signaling pathway, p53 signaling pathway, and PI3K-Akt signaling pathway, might be involved