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Growth/Differentiation Factor 15 Causes Tgfβ-Activated Kinase 1

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Growth/Differentiation Factor 15 Causes Tgfβ-Activated Kinase 1 Skeletal Muscle Thorax: first published as 10.1136/thoraxjnl-2017-211440 on 15 December 2018. Downloaded from ORIGINAL ARTICLE Growth/differentiation factor 15 causes TGFβ- activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension Benjamin E Garfield,1,2 Alexi Crosby,3 Dongmin Shao,1,2 Peiran Yang,3 Cai Read,3 Steven Sawiak,3 Stephen Moore,3 Lisa Parfitt,2 Carl Harries,2 Martin Rice,3 Richard Paul,4 Mark L Ormiston,5 Nicholas W Morrell,3 Michael I Polkey,4 Stephen John Wort,1,2 Paul R Kemp1 ► Additional material is ABSTRact published online only. To view Introduction Skeletal muscle dysfunction is a Key messages please visit the journal online (http:// dx. doi. org/ 10. 1136/ clinically important complication of pulmonary arterial thoraxjnl- 2017- 211440). hypertension (PAH). Growth/differentiation factor What is the key question? 15 (GDF-15), a prognostic marker in PAH, has been ► What is the association between growth/ For numbered affiliations see associated with muscle loss in other conditions. We differentiation factor 15 (GDF-15) and muscle end of article. aimed to define the associations ofG DF-15 and muscle wasting in pulmonary arterial hypertension? Correspondence to wasting in PAH, to assess its utility as a biomarker of What is the bottom line? Dr Stephen John Wort, Section muscle loss and to investigate its downstream signalling ► GDF-15 is a responsive biomarker for muscle of Vascular Biology, NHLI, pathway as a therapeutic target. wasting in pulmonary arterial hypertension Imperial College London, Methods GDF-15 levels and measures of muscle size London SW3 6PT, UK; that acts through TGFβ-activated kinase s. wort@ imperial. ac. uk and strength were analysed in the monocrotaline (MCT) 1, a potential target for direct therapeutic rat, Sugen/hypoxia mouse and in 30 patients with PAH. intervention. SJW and PRK contributed In C2C12 myotubes the downstream targets of GDF- equally. 15 were identified.T he pathway elucidated was then Why read on? antagonised in vivo. ► GDF-15 is a prognostic marker in a wide range Received 19 December 2017 Results Circulating GDF-15 levels correlated with of conditions. Here we shed new light on ways Revised 24 September 2018 in which we might use GDF-15 to identify Accepted 1 October 2018 tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=−0.61, p=0.003). In patients with PAH, those at increased risk of muscle wasting and http://thorax.bmj.com/ plasma GDF-15 levels of <564 pg/L predicted those on ways of treating this ubiquitous outcome of with preserved muscle strength with a sensitivity and chronic disease. specificity of ≥80%.I n vitro GDF-15 stimulated an increase in phosphorylation of TGF -activated kinase 1 β Muscle strength and size is determined by the (TAK1). Antagonising TAK1, with 5(Z)-7-oxozeaenol, in balance between protein synthesis and breakdown.6 vitro and in vivo led to an increase in fibre diameter and In the quadriceps of patients with PAH there is an a reduction in mRNA expression of atrogin-1 in both upregulation of the proatrophic ubiquitin ligases C2C12 cells and in the TA of animals who continued to atrogin-1 and Muscle RING finger protein-1 on September 29, 2021 by guest. Protected copyright. grow. Circulating GDF-15 levels were also reduced in (MuRF1), while prohypertrophic protein kinase those animals which responded to treatment. B (AKT),3 a component of the insulin-like growth Conclusions Circulating GDF-15 is a biomarker of factor 1 (IGF-1) pathway,6 is downregulated.3 The muscle loss in PAH that is responsive to treatment. TAK1 monocrotaline (MCT) rat, a model of PAH, has inhibition shows promise as a method by which muscle smaller hindlimb muscle fibre cross sectional area atrophy may be directly prevented in PAH. (CSA), a reduction in contractile function and a Trial registration number NCT01847716; Results. tendency to overexpress atrogin-1 and MuRF1, ► http:// dx. doi. org/ 10.1136/ 7 8 thoraxjnl- 2018- 212680 when compared with control treated animals. The transforming growth factor β (TGFβ) proteins have been implicated in the development INTRODUCTION of both PAH and muscle wasting.9 10 One TGFβ © Author(s) (or their Even with the emergence of modern pulmo- protein, growth/differentiation factor (GDF-15) employer(s)) 2018. Re-use nary vasodilators the morbidity and mortality for permitted under CC BY. has been shown to be a prognostic marker in idio- 11 Published by BMJ. patients with pulmonary arterial hypertension pathic (I)PAH. GDF-15 has also been associated 1 (PAH) remains high. Skeletal muscle dysfunction is with muscle wasting in intensive care unit-ac- To cite: Garfield BE, 12–15 as an important complication and target for thera- quired weakness (ICUAW), COPD and cancer. Crosby A, Shao D, et al. 2 3 16 peutic intervention in patients with PAH. Despite GDF-15 has been shown to suppresses appetite, Thorax Epub ahead of print: 4 [please include Day Month the effects of rehabilitation, there remains a ratio- via its recently discovered receptor the glial cell Year]. doi:10.1136/ nale for developing anabolic agents5 which might line-derived neurotrophic factor family receptor-al- thoraxjnl-2017-211440 improve patients’ outcomes. pha-like (GFRAL)17 as well as directly affecting Garfield BE, et al. Thorax 2018;0:1–13. doi:10.1136/thoraxjnl-2017-211440 1 Skeletal Muscle Thorax: first published as 10.1136/thoraxjnl-2017-211440 on 15 December 2018. Downloaded from muscle by increasing the local expression of atrogin-1 and Fibre diameter measurement and immunohistochemistry MuRF1.12 13 The downstream signalling pathway through which Tibialis anterior (TA) muscle fibre diameter from each animal GDF-15 acts in muscle remains to be elucidated,15 although one was analysed.13 23 In the observational study, ice crystal potential target is the TGFβ-activated kinase 1 (TAK1), nuclear damage meant samples were available in 11/16 MCT rats factor κB (NFκB) pathway.18 Delineating and then targeting the and 12/14 control animals. Sections of lung tissue and TA pathways through which GDF-15 acts in muscle is a potential from five control and five MCT-treated rats were analysed method to prevent or treat muscle wasting in PAH as well as for GDF-15, and in the case of the lung, smooth muscle actin other conditions where GDF-15 is a marker of prognosis. expression.22 We therefore aimed to determine the local and systemic expres- sion profiles of GDF-15 in animal models of PAH, to investigate Human study the association of GDF-15 and muscle wasting in patients with Ethical approval was granted by the REC (13/LO0481) and PAH and to explore the mechanism of action of GDF-15 with a by the Royal Brompton Hospital ( www. clinicaltrials.gov view to developing a therapeutic intervention. NCT01847716). In 30 patients with PAH, recruited from the Royal Brompton Hospital, we measured quadriceps maximal volitional capacity (QMVC) and rectus femoris cross-sectional METHODS 24 25 area (RFCSA) concurrently. QMVC was expressed as a func- The online supplementary material contains full experimental 26 details. tion of body mass index (BMI). All patients initially enrolled also had their physical activity level (PAL) assessed with the SenseWear Armband. Twenty-five had adequate PAL data.27 All Animal experiments patients also underwent 6 min walk distance (6MWD),28 echo- Animal experiments were approved by the local animal welfare cardiographic assessment and had blood taken for brain natri- ethics committee and the Home Office (PPL 70/8850). uretic peptide (BNP) and GDF-15 levels. Observational study Statistics Thirty male Sprague-Dawley rats received a single subcutaneous Statistics were calculated using GraphPad Prism (V.5, USA). injection of MCT (40 mg/kg) (n=16) or vehicle control (n=14). Data are presented as mean±SD or median and IQR. Student’s Food intake was monitored on a per cage basis. Animals were t-test, Mann-Whitney U test, Pearson or Spearman analysis, Fish- humanely killed at 4 weeks, immediately after MRI (n=3 each er’s exact test and analysis of variance (ANOVA) or repeated group) and haemodynamic assessment.19 measures ANOVA with Bonferroni correction or Kruskal-Wallis with Dunn’s analysis were used to compare groups, depen- dent on the type and distribution of the data. For correlations 5(Z)-7-oxozeaenol (Merck Millipore) study strong associations were defined as those with an r>0.5. The Twenty rats were treated with MCT and 10 with control injec- proportion of muscle fibres in 5 μm increments was analysed in tions as above. After 2 weeks 10 of the animals in the MCT MCT 5(Z)-7-oxozeaenol experiment as previously described.23 group were treated with 5(Z)-7-oxozeanol 0.5 mg/kg/day Receiver operating characteristic (ROC) curves were constructed http://thorax.bmj.com/ intraperitoneally for 9 days, after which they were humanely for: rats continuing to grow (reaching their maximum weight on 19 20 killed. One animal in the MCT TAK1i group was excluded the last day of the experiment and not plateaued); patients with from analysis as it had to be humanely killed before the treat- retained muscle strength (QMVC/BMI>1.5—based on hospital- ment end point. isation data from the same cohort, online supplementary figure E1). Sugen/hypoxia mouse model Five Sugen/hypoxia, five hypoxic and five normoxic control RESUlts 21 mice were treated as previously described. They were humanly The MCT rat and Sugen/hypoxia mouse models of pulmonary on September 29, 2021 by guest. Protected copyright. killed after 3 weeks. hypertension are associated with muscle loss All MCT rats and Sugen/hypoxia mice developed pulmonary hypertension (PH) (online supplementary figure E2).
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