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:
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.
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).
In patients with PAH serum GDF-15 correlated significantly with QMVC/BMI (rho=-0.41, p<0.05)
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.
- Copyright ©ERS 2015
