The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Systemic administration of propeptides attenuates activin A-induced cachetic wasting (#94)

Kelly L Walton 1 , Justin L Chen 1 2 , Queenie Lee 1 2 , Emily Kelly 1 , Mylinh La 3 , Louis Lu 3 , George Lovrecz 3 , Adam Hagg 1 2 , Timothy Colgan 2 , Hongwei Qian 2 , Paul Gregorevic 2 , Craig A Harrison 1
  1. Monash University, Clayton, VIC, Australia
  2. Muscle Research & Therapeutics Development, Baker IDI, Melbourne, VIC, Australia
  3. CSIRO Material Sciences and Engineering, Clayton, VIC, Australia

Activin abundance in cancers promotes lethal ‘cachetic’ wasting of muscle, irrespective of tumour progression. In excess, activins A and B can hijack the myostatin signalling pathway, triggering a protein degradative pathway bias, ultimately resulting in muscle atrophy. In a recent study, we demonstrated that the co-inhibition of activin- and myostatin-induced signalling using virally (AAV) delivered propeptides (natural polypeptide inhibitors) could induce profound muscle hypertrophy in healthy mice. Additionally, the propeptides effectively attenuated localised muscle wasting in models of dystrophy and cancer cachexia. In this follow-up study, we sought to examine the ability of systemically administered propeptides to rescue activin A-induced cachetic wasting in mice. To address this, we first transplanted stable CHO cells expressing activin A (CHO:ActA) into the quadriceps of immunogenic mice. Establishment of CHO:ActA tumours elevated circulating activin A concentrations by 85-fold, and caused a 16% loss of starting body mass, and a 10% reduction in lean mass at 12 days post-implantation. In alignment with our previous findings, we found that CHO:ActA-induced muscle wasting could be attenuated using AAV delivered activin A propeptides. Significantly, here we show that systemic delivery of the activin A propetides can rescue CHO:ActA induced loss of body mass by 50%, lean mass by 70%, and protect from CHO:ActA mediated fat loss. It was also found that systemically delivered propeptides could protect the heart, liver, kidney and brown fat from activin A insult. This is the first study to demonstrate that systemic propeptide therapy can effectively attenuate chronic activin A insult in multiple tissues.