The role of growth and differentiation factor 15 (GDF-15) in the development of skeletal muscle wasting in pulmonary arterial hypertension (PAH)

Abstract

Introduction: Skeletal muscle wasting is emerging as an important complication of PAH. GDF-15, a TGFbeta ligand, has been implicated in the development of muscle wasting and is a marker of prognosis in PAH. It may be a potential target for therapeutic intervention. Methods: 1. Serum, tibialis anterior (TA) muscle and lung GDF-15 levels in the monocrotaline (MCT) rat were studied by ELISA and qPCR. As was TA fibre diameter. 2. C2C12 myotubes were treated with GDF-15 +/- TGFbeta activated kinase inhibitor (TAK1i) after which mRNA was harvested for qPCR 3. Serum GDF-15 levels and quadriceps strength (QMVC/BMI) was measured in 29 patients with PAH. Results: 1. Serum GDF-15 and lung mRNA levels of GDF-15 were raised in MCT rats compared to controls (p<0.01, p<0.05 respectively). These were strongly correlated (r= 0.79, p<0.01). MCT rats had a lower TA fibre diameter than controls (p<0.001). Serum GDF-15 levels correlated significantly with TA fibre diameter in this model. 2. GDF-15 treatment of myotubes resulted in an increased expression of ubiquitin ligase atrogin (p<0.05). This was prevented by co-treatment with a TAK1i (p<0.05). 3. In patients with PAH serum GDF-15 correlated significantly with QMVC/BMI (rho=-0.41, p<0.05) ![Figure][1] Conclusions: Serum GDF-15 is associated with muscle dysfunction in PAH. GDF-15 seems to act through TAK1 which may be a future therapeutic target. [1]: pending:yes