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Cited by 40Muscle Physiology and DisordersChronic Obstructive Pulmonary Disease (COPD) ResearchCardiovascular and exercise physiology

Network Modules Uncover Mechanisms of Skeletal Muscle Dysfunction in COPD Patients

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Tényi, Ákos, Cano, Isaac, Marabita, Francesco, Kiani, Narsis, Kalko, Susana G., Barreiro, Esther, de Atauri, Pedro, Cascante, Marta +2 more·2018·Journal of Translational Medicine
DOI 10.1186/s12967-018-1405-yPMC PMC5819708
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Abstract

Background: 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. Methods: We characterized the transcriptionally active network modules of interacting proteins in the vastus lateralis of COPD patients (n = 15, FEV 1 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. Results: 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 2 peak, Watts peak, BODE index and blood lactate levels) (P < 0.05 each), but not with lung function (FEV 1). 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. Conclusion: 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

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  • IFN-γ has been reported as unchanged at the protein level in COPD quadriceps compared to controls, while a recent transcriptional analysis shows a globally downregulated interferon response in COPD quadriceps.

    “IFN-γ has been reported as unchanged at the protein level in COPD quadriceps compared to controls [27]. However, a recent transcriptional analysis shows a globally downregulated interferon response in COPD quadriceps [56].”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [56]

    The Results section on skeletal muscle alterations at rest reports systematic down-regulation of IFIT genes in an interferon-response module. The Methods identify the sampled muscle as the vastus lateralis, part of the quadriceps. The paper does not establish that the interferon response as a whole was globally downregulated; the separate protein-level claim is cited to [27], not this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Disruption of calcium homeostasis in COPD quadriceps is represented by downregulation of S100A1, which could lead to abnormal sarcoplasmic reticulum Ca2+ content and fluxes, impacting muscle contractility.

    “The disruption of calcium homeostasis was represented by the downregulation of S100A1 gene, which could lead to abnormal sarcoplasmic reticulum Ca2+ content and fluxes, impacting muscle contractility [56].”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [56]

  • The creatine metabolism pathway is significantly altered in COPD quadriceps with downregulation of GAMT, GATM, CKB, and CKMT2.

    “Specifically, the creatine metabolism pathway was significantly altered with downregulation of two genes related to creatine synthesis (GAMT, GATM) and two creatine kinase genes (CKB, CKMT2).”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [56]

  • A recent study using microarrays and gene ontology algorithms identified abnormalities in creatine metabolism and calcium homeostasis in COPD quadriceps, significantly associated with exercise capacity.

    “Another recent study [56], using microarrays and gene ontology algorithms to detect network modules in COPD and healthy quadriceps, identified abnormalities in creatine metabolism and calcium homeostasis, which were significantly associated with exercise capacity.”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [56]

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Authors
Tényi, Á., Cano, I., Marabita, F., Kiani, N., Kalko, S. G., Barreiro, E., de Atauri, P., Cascante, M., Gomez-Cabrero, D., & Roca, J.
Affiliations
  • Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES)
  • Karolinska Institutet (SE)
  • Universitat Pompeu Fabra (ES)
  • Institut de Biomedicina de la Universitat de Barcelona (ES)
Corresponding author
  • Tényi, Ákos
  • Roca, Josep
ORCID
Venue
Journal of Translational Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-02-20
Volume
16
Issue
1
Pages
34-34
ISSN
1479-5876 (ISSN-L)
DOI
10.1186/s12967-018-1405-y
PMC
PMC5819708
OpenAlex
W2796186950
Cited by
40
References
5
Citations by year
2026: 2 · 2025: 2 · 2024: 14 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 5
FWCI
1.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Translational Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
Funders
H2020 Societal Challenges (689802)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
  • Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
Keywords
chronic obstructive pulmonary disease, skeletal muscle dysfunction, vastus lateralis, protein-protein interaction network, network modules, endurance training, muscle energy metabolism, creatinine metabolism, calcium homeostasis, oxidative stress, inflammation, exercise capacity, muscle remodeling, plasma metabolomics, muscle training
MeSH terms
Aged, Female, Humans, Male, Rest, Muscle, Skeletal, Pulmonary Disease, Chronic Obstructive, Gene Regulatory Networks, Metabolomics

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