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

Thorax. 2019 Feb;74(2):164-176. doi: 10.1136/thoraxjnl-2017-211440. Epub 2018 Dec 15.


Introduction: Skeletal 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.

Methods: GDF-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.

Results: Circulating 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.

Conclusions: Circulating 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.

Keywords: exercise; primary pulmonary hypertension.

Publication types

  • Clinical Trial
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Biomarkers / metabolism
  • Blotting, Western
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Growth Differentiation Factor 15 / metabolism*
  • Humans
  • Hypertension, Pulmonary / complications*
  • Hypertension, Pulmonary / metabolism
  • Immunohistochemistry
  • MAP Kinase Kinase Kinases / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Muscle, Skeletal / metabolism
  • Muscular Atrophy / etiology*
  • Muscular Atrophy / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*


  • Biomarkers
  • Growth Differentiation Factor 15
  • Transforming Growth Factor beta
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7

Associated data