Network modules uncover mechanisms of skeletal muscle dysfunction in COPD patients

• Published in: Journal of translational medicine Vol. 16; no. 1; p. 34
• Main Authors: Tényi, Ákos, Cano, Isaac, Marabita, Francesco, Kiani, Narsis, Kalko, Susana G, Barreiro, Esther, de Atauri, Pedro, Cascante, Marta, Gomez-Cabrero, David, Roca, Josep
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20-02-2018; BioMed Central; BMC
• Subjects: Aged; Chronic obstructive pulmonary disease; Development and progression; Exercise; Exercise training; Female; Gene modules; Gene Regulatory Networks; Health aspects; Humans; Lung diseases, Obstructive; Malalties obstructives; Male; Medicin och hälsovetenskap; Metabolomics; Muscle, Skeletal - physiopathology; Muscles; Muscular weakness; Physiological aspects; Prognosis; Pulmonary Disease, Chronic Obstructive - blood; Pulmonary Disease, Chronic Obstructive - genetics; Pulmonary Disease, Chronic Obstructive - physiopathology; Pulmons; Rest; Systems medicine; Gene modules; Chronic obstructive pulmonary disease; Exercise training; Muscular weakness; Systems medicine
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-018-1405-y

Chronic obstructive pulmonary disease (COPD) patients often show skeletal muscle dysfunction that has a prominent negative impact on prognosis. The study aims to further explore underlying mechanisms of skeletal muscle dysfunction as a characteristic systemic effect of COPD, potentially modifiable with preventive interventions (i.e. muscle training). The research analyzes network module associated pathways and evaluates the findings using independent measurements.
We characterized the transcriptionally active network modules of interacting proteins in the vastus lateralis of COPD patients (n = 15, FEV
46 ± 12% pred, age 68 ± 7 years) and healthy sedentary controls (n = 12, age 65 ± 9  years), at rest and after an 8-week endurance training program. Network modules were functionally evaluated using experimental data derived from the same study groups.
At baseline, we identified four COPD specific network modules indicating abnormalities in creatinine metabolism, calcium homeostasis, oxidative stress and inflammatory responses, showing statistically significant associations with exercise capacity (VO
peak, Watts peak, BODE index and blood lactate levels) (P < 0.05 each), but not with lung function (FEV
). Training-induced network modules displayed marked differences between COPD and controls. Healthy subjects specific training adaptations were significantly associated with cell bioenergetics (P < 0.05) which, in turn, showed strong relationships with training-induced plasma metabolomic changes; whereas, effects of training in COPD were constrained to muscle remodeling.
In summary, altered muscle bioenergetics appears as the most striking finding, potentially driving other abnormal skeletal muscle responses. Trial registration The study was based on a retrospectively registered trial (May 2017), ClinicalTrials.gov identifier: NCT03169270.