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@article{Garfield:2019:10.1136/thoraxjnl-2017-211440,
author = {Garfield, B and Crosby, A and Shao, D and Yang, P and Read, C and Sawaik, S and Moore, S and Parfitt, L and Harries, C and Rice, M and Paul, R and Ormiston, M and Morrell, N and Polkey, M and Wort, SJ and Kemp, P},
doi = {10.1136/thoraxjnl-2017-211440},
journal = {Thorax},
pages = {164--176},
title = {Growth/differentiation factor 15 causes TGFβ activated kinase 1 dependent muscle atrophy in pulmonary arterial hypertension},
url = {http://dx.doi.org/10.1136/thoraxjnl-2017-211440},
volume = {74},
year = {2019}
}

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TY  - JOUR
AB  - 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.
AU  - Garfield,B
AU  - Crosby,A
AU  - Shao,D
AU  - Yang,P
AU  - Read,C
AU  - Sawaik,S
AU  - Moore,S
AU  - Parfitt,L
AU  - Harries,C
AU  - Rice,M
AU  - Paul,R
AU  - Ormiston,M
AU  - Morrell,N
AU  - Polkey,M
AU  - Wort,SJ
AU  - Kemp,P
DO  - 10.1136/thoraxjnl-2017-211440
EP  - 176
PY  - 2019///
SN  - 1468-3296
SP  - 164
TI  - Growth/differentiation factor 15 causes TGFβ activated kinase 1 dependent muscle atrophy in pulmonary arterial hypertension
T2  - Thorax
UR  - http://dx.doi.org/10.1136/thoraxjnl-2017-211440
UR  - http://hdl.handle.net/10044/1/65196
VL  - 74
ER  -

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