{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:20:18Z","timestamp":1788348018494,"version":"build-2803163510"},"reference-count":40,"publisher":"BMJ","issue":"2","funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Thorax"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Circulating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=\u22120.61, p=0.003). In patients with PAH, plasma GDF-15 levels of &lt;564\u2009pg\/L predicted those with preserved muscle strength with a sensitivity and specificity of \u226580%. In vitro GDF-15 stimulated an increase in phosphorylation of TGF\u03b2-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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration number<\/jats:title><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"NCT01847716\" ext-link-type=\"clintrialgov\" specific-use=\"clinicaltrial results\">NCT01847716<\/jats:ext-link>; Results.<\/jats:p><\/jats:sec>","DOI":"10.1136\/thoraxjnl-2017-211440","type":"journal-article","created":{"date-parts":[[2018,12,15]],"date-time":"2018-12-15T22:25:20Z","timestamp":1544912720000},"page":"164-176","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":53,"title":["Growth\/differentiation factor 15 causes TGF\u03b2-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension"],"prefix":"10.1136","volume":"74","clinical-trial-number":[{"clinical-trial-number":"nct01847716","registry":"10.18810\/clinical-trials-gov","type":"results"},{"clinical-trial-number":"nct01847716","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Benjamin 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