Targeting activin to counteract muscle wasting and cachexia — ASN Events

Targeting activin to counteract muscle wasting and cachexia (#189)

Justin Chen 1 , Kelly Walton 1 , Paul Gregorevic 2 , Craig Harrison 1
  1. Prince Henrys Institute , Clayton, VIC, Australia
  2. Baker IDI Heart and Diabetes Institute, Melbourne, Australia

Muscle wasting is observed during ageing and disuse, but is also associated with diseases, including muscular dystrophy, sepsis, renal failure, AIDS, diabetes and cancer. In this latter group of conditions, muscle loss is the most debilitating aspect of the syndrome of cachexia, a condition characterised by pronounced weight loss, muscle weakness, anaemia, insulin resistance, and extreme fatigue. Recent evidence suggests that signalling via the activin type II receptor (ActRIIB) plays a dominant role in the aetiology of cachexia. In multiple cancer cachexia models, pharmacological blockade of the ActRIIB pathway not only prevented further muscle wasting, but restored previous muscle loss. ActRIIB mediates the signalling of a subset of transforming growth factor-β (TGF-β) ligands, including myostatin, activin A, activin B and GDF-11. To show a causal link between increased activin signalling and muscle wasting, we utilised adeno-associated viral vectors (AAV) to express activin A in the righttibialis anterior (TA) muscles of C57BL/6 mice. At the lowest viral dose (109 viral genomes), activin A caused a rapid and sustained decrease in muscle mass, which was characterised by inactivation of protein synthesis and activation of protein degradation pathways. At higher viral doses (2x1011 viral genomes), the mass of the treated TA muscle decreased by 60%, circulating activin A levels rose 12-fold and significant decreases were observed in total body, liver and testes masses. These highly catabolic effects of activin A identify it as a likely mediator of cancer cachexia. To this end, we have recently developed the first specific activin A antagonist and shown in vivo that it is capable of inhibiting activin-induced muscle wasting.