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Title: Growth and differentiation factor 15 causes skeletal muscle wasting in pulmonary arterial hypertension through actions on transforming growth factor β activated kinase 1
Author: Garfield, Ben
ISNI:       0000 0004 7223 5626
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Muscle wasting is an important complication of a wide range chronic diseases. Pulmonary arterial hypertension (PAH) is no different. Novel targets and treatments are required to help improve outcomes in patients with PAH complicated by muscle wasting. GDF-15 is prognostic marker in PAH and has been shown to cause muscle wasting in vitro and in vivo. The pathway through which GDF-15 acts in muscle cells is not established. I used a human study, animal models of PAH; the monocrotaline (MCT) rat; and Sugen/hypoxia mouse, as well as C2C12 muscle cells to determine whether GDF-15 and its downstream signals may be important in the development of muscle wasting and low physical activity in PAH. Muscle wasting and low physical activity were associated with poor outcomes in a population of patients with PAH. Circulating GDF-15 levels were associated with markers of muscle strength and size in 2 animal models and in patients with PAH. In the MCT rat the pulmonary vasculature was an important site of production of GDF-15. GDF-15 acted by increasing the expression of ubiquitin ligases, which are involved in muscle wasting. GDF-15 decreased the activity of SMAD 1, 5 whilst increasing transforming growth factor β activated kinase 1 (TAK1) phosphorylation in muscle cells. Antagonising TAK1 with 5(Z)-7-oxozeaenol partially prevented muscle loss and rises in ubiquitin ligase expression in muscle cells and prevented weight loss in some MCT rats treated for 9 days with the drug. Muscle wasting and low physical activity are potentially modifiable risk factors for poor prognosis in PAH. GDF-15 may be a useful biomarker of muscle loss in PAH. Antagonising GDF-15 through its downstream mediator TAK1 requires further evaluation in animal models and patients with PAH to establish its usefulness in clinical practice.
Supervisor: Wort, Stephen J. ; Kemp, Paul ; Polkey, Michael Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral