> Details

Garfield, Benjamin E; Crosby, Alexi; Shao, Dongmin; Yang, Peiran; Read, Cai; Sawiak, Steven; Moore, Stephen; Parfitt, Lisa; Harries, Carl; Rice, Martin; Paul, Richard; Ormiston, Mark L; Morrell, Nicholas W; Polkey, Michael I; Wort, Stephen John; Kemp, Paul R

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

Reference
management

Bookmarks

Remove from
bookmarks

Share this on Whatsapp

Close

Bookmarks



You can manage bookmarks using lists, please log in to your user account for this.
  • Media type: E-Article
  • Title: Growth/differentiation factor 15 causes TGFβ-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension
  • Contributor: Garfield, Benjamin E; Crosby, Alexi; Shao, Dongmin; Yang, Peiran; Read, Cai; Sawiak, Steven; Moore, Stephen; Parfitt, Lisa; Harries, Carl; Rice, Martin; Paul, Richard; Ormiston, Mark L; Morrell, Nicholas W; Polkey, Michael I; Wort, Stephen John; Kemp, Paul R
  • Published: BMJ, 2019
  • Published in: Thorax, 74 (2019) 2, Seite 164-176
  • Language: English
  • DOI: 10.1136/thoraxjnl-2017-211440
  • ISSN: 0040-6376; 1468-3296
  • Origination:
  • Footnote:
  • Description: 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 numberNCT01847716; Results.