FP25-5 Targeting Activin to Counteract Muscle Wasting and Cachexia

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP25-Signaling Originating from Membrane Receptors
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:05 AM
Room 133 (Moscone Center)

Poster Board SUN-394
Justin L Chen*1, Kelly Louise Walton1, Sara Layla Al-Musawi2, Paul Gregorevic3 and Craig Anthony Harrison4
1Prince Henry's Institute of Medical Research, Clayton, VIC, Australia, 2Prince Henry's Institute of Medical Research, Clayton VIC, Australia, 3Baker IDI Heart and Diabetes Institute, Melbourne, Australia, 4Prince Henry's Institute of Medical Research, Clayton, Australia
Cancer cachexia is a state of pronounced weight loss, frailty and fatigue, characterised by a profound loss of muscle and fat mass, insulin resistance and anaemia. In advanced cancers, up to 80% of patients exhibit cachectic symptoms, and remarkably 25% of cancer-related mortalities derive from cachexia rather than direct tumour burden. As such, cancer cachexia remains a major unmet medical need. Recent evidence suggests that signalling through the activin type II receptor (ActRIIB) plays a dominant role in the aetiology of cachexia. ActRIIB mediates the signalling of a subset of transforming growth factor-β ligands, including myostatin, activin A, activin B and GDF-11. In multiple cancer cachexia models, pharmacological blockade of the ActRIIB pathway not only prevented further muscle wasting, but restored previous muscle loss. In a screen of human cancer cell lines, we found that activin A was highly expressed in several aggressive or metastatic cells. We hypothesise that the over-expression of activin A can induce muscle wasting and cachexia and that targeting its actions will reverse these effects. To show a causal link between increased activin A and muscle wasting, we utilised adeno-associated viral vectors (AAV) to express activin A in the right hindlimb tibialis anterior (TA) muscle of male C57Bl/6 mice; the left TA muscle was injected with an empty AAV as a control. Increasing vector doses (109 – 2x1011) resulted in a rapid, dose-dependent decrease in the mass of the injected TA muscle, and after 4 weeks, there was a significant reduction in muscle fibre size. Western blot analysis indicated that activin A increased the phosphorylation of the transcription factor Smad3 and correlated with dephosphorylation of Akt, p70S6K and S6RP, suggesting inhibition of the protein synthesis pathway. Concomitantly, qPCR analysis indicated an upregulation of atrogin-1 transcripts, a key ubiquitin ligase that regulates protein degradation. At the higher viral doses, hindlimb muscles surrounding the TA also decreased in mass. In these mice, circulating activin A levels increased up to 12-fold and caused significant decreases in liver, testes and total body mass. Our findings demonstrate the importance of blocking activin A activity in cachexia and, to this end, we have recently developed the first specific activin antagonist. This antagonist completely prevents activin-induced muscle wasting in vivo. Current studies are evaluating its efficacy to restore muscle mass in a murine model of cancer cachexia.

Nothing to Disclose: JLC, KLW, SLA, PG, CAH

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