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

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 TGFß-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.

Impulsivity and compulsivity are differentially associated with automaticity and routine on the Creature of Habit Scale.

Habits may develop when meaningful action patterns are frequently repeated in a stable environment. We measured the differing tendencies of people to form habits in a population sample of n = 533 using the Creature of Habit Scale (COHS). We confirmed the high reliability of the two latent factors measured by the COHS, automaticity and routines. Whilst automatic behaviours are triggered by context and do not serve a particular purpose or goal, routines often have purpose, and because they have been performed so often in a given context, they become automatic only after their action sequence has been activated. We found that both types of habitual behaviours are influenced by the frequency of their occurrence and they are differentially influenced by personality traits. Compulsive personality is associated with an increase in both aspects of habitual tendency, whereas impulsivity is linked with increased automaticity, but reduced routine behaviours. Our findings provide further evidence that the COHS is a useful tool for understanding habitual tendencies in the general population and may inform the development of therapeutic strategies that capitalise on functional habits and help to treat dysfunctional ones.