Evidence map›Paper›PMID 30554141›Full record

Observational studyThorax2019

Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension.

Benjamin E Garfield, Alexi Crosby, Dongmin Shao, Peiran Yang, Cai Read, Steven Sawiak, Stephen Moore, Lisa Parfitt, Carl Harries, Martin Rice and 6 more

Registry-linked trialOpen access · bronzeAbstract readObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in Thorax, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01847716 (Transforming Growth Factor Beta Signalling in the Development of Muscle Weakness in Pulmonary Arterial Hypertension), which is not on this map. Cited by 38 papers.

0numbers the graph read from it
0cells of the map it votes in
38citing papers in PubMed
3.6field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01847716 terminatednot on this map

Transforming Growth Factor Beta Signalling in the Development of Muscle Weakness in Pulmonary Arterial Hypertension

TypeobservationalSponsorImperial College LondonRan2013 to 2016Enrolled33ConditionsMuscle Weakness, Pulmonary Arterial Hypertension
3 · Its place in the literature

Who cites it

38 citing papers in PubMed, 52 citations in OpenAlex.

  1. Review
  2. Article
  3. Review
  4. Cancer cachexia: molecular basis and therapeutic advances.Signal transduction and targeted therapy · 2026
    Review
  5. Review
  6. Review
  7. Observational
  8. Article
  9. Review
  10. Review
  11. Article
  12. Review
  13. Article
  14. Review
  15. Article
  16. Review
  17. Review
  18. Emerging role of TAK1 in the regulation of skeletal muscle mass.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023
    Review
  19. Article
  20. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

16 authors at 5 institutions in 4 countries.

Benjamin E GarfieldNational Heart and Lung Institute, Imperial College London, London, UK.
Alexi CrosbyDepartment of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Dongmin ShaoNational Heart and Lung Institute, Imperial College London, London, UK.
Peiran YangDepartment of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Cai ReadDepartment of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Steven SawiakDepartment of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Stephen MooreDepartment of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Lisa ParfittNational Pulmonary Hypertension Service, Royal Brompton Hospital, London, UK.
Carl HarriesNational Pulmonary Hypertension Service, Royal Brompton Hospital, London, UK.
Martin RiceDepartment of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Richard PaulNIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, UK.
Mark L OrmistonDepartments of Biomedical and Molecular Sciences, Medicine and Surgery, Queen's University, Kingston, Ontario, Canada.
Nicholas W MorrellDepartment of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Michael I PolkeyNIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, UK.
Stephen John Wort *National Heart and Lung Institute, Imperial College London, London, UK.
Paul R Kemp *National Heart and Lung Institute, Imperial College London, London, UK.ORCID 0000-0001-8975-7293
University of Cambridge · GBPulmonary Hypertension Association · USRoyal Brompton & Harefield NHS Foundation Trust · GBLung Institute · USQueen's University · CA

Funding

British Heart Foundation PG/13/91/30579British Heart Foundation RG/13/4/30107Department of HealthMedical Research Council MR/K023918/1Wellcome Trust
6 · The paper itself

Abstract

introductionSkeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target.

methodsGDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo.

resultsCirculating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=-0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of <564 pg/L predicted those with preserved muscle strength with a sensitivity and specificity of ≥80%. In vitro GDF-15 stimulated an increase in phosphorylation of TGFβ-activated kinase 1 (TAK1). Antagonising TAK1, with 5(Z)-7-oxozeaenol, in vitro and in vivo led to an increase in fibre diameter and a reduction in mRNA expression of atrogin-1 in both C2C12 cells and in the TA of animals who continued to grow. Circulating GDF-15 levels were also reduced in those animals which responded to treatment.

conclusionsCirculating GDF-15 is a biomarker of muscle loss in PAH that is responsive to treatment. TAK1 inhibition shows promise as a method by which muscle atrophy may be directly prevented in PAH. TRIAL REGISTRATION NUMBER: NCT01847716; Results.

Indexed as

Growth Differentiation Factor 15Hypertension, PulmonaryMAP Kinase Kinase KinasesMuscular AtrophyTransforming Growth Factor betaAdultAnimalsBiomarkersBlotting, WesternEnzyme-Linked Immunosorbent AssayFemaleHumansImmunohistochemistryMaleMAP Kinase Kinase Kinase 7MiceBiomarkersGrowth Differentiation Factor 15MAP Kinase Kinase Kinase 7MAP Kinase Kinase KinasesTransforming Growth Factor betaexerciseprimary pulmonary hypertension

Identifiers

PMID30554141
PMCPMC6467240
OpenAlexW2905205873

What OpenQuestion holds

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LicenceCC BY
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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.