Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Characterisation of a novel modulator of TGF-b signalling in muscle (#172)

Hugo WG Herron-Vellacott 1 , Jackson C Hawken 1 , Adam Hagg 1 , Ying Wang 2 , Daniel J Bernard 2 , Kelly L Walton 1 3
  1. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
  2. Department of Pharmacology and Therapeutics, University of McGill, Montreal, Quebec, Canada
  3. Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia

Several members of the transforming growth factor-b (TGF-b) family including growth and differentiation factors -8 and -11 (GDF8 and GDF11), the activins, and bone morphogenetic proteins (BMPs) play essential roles in the regulation of muscle homeostasis. We identified a novel TGF-b type III-like receptor present in skeletal muscle that binds select TGF-b ligands. Here, we examined if and how the receptor modulates TGF-b signalling. In heterologous HEK293 cells, GDF8 and GDF11-stimulated SMAD2 phosphorylation was significantly reduced (-36% and -48% respectively) upon ectopic expression of the receptor. As these ligands regulate muscle physiology, we next examined the effects of receptor over-expression in mice.  An adeno-associated viral vector (AAV) expressing the receptor (AAV:receptor) or control AAV (AAV:iRFP) was administered (1x109-5x109vg) to the tibialis anterior (TA) muscles of 8-week old healthy male wild-type C57BL/6J mice. At 4-weeks post injection, TAs were harvested for histological and molecular assessment. TAs injected with AAV:receptor were on average significantly reduced in mass relative to the TAs injected with control AAV:iRFP (-8.4%, n=5, *p<0.05) owing to muscle fibre atrophy. Receptor over-expression suppressed the BMP-driven SMAD1/5/8 signalling pathway whilst simultaneously upregulating the SMAD2/3 pathway to trigger an atrophic response in muscle, as assessed by western blot analysis of TA muscle protein lysates. Collectively, the findings indicate that overexpression of the novel type III-like receptor in muscle may promote atrophy via modulation of TGF-b signalling. As the receptor is present in skeletal muscle, our findings suggest that it may act as physiological regulator of muscle homeostasis via interactions with select TGF-b ligands.