Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting
Cancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers SB431542 and GW788388 in preventing muscle wasting, and explored synergy with IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 and LR3 IGF-I. A C26-CD2F1 cachexia model was used to induce cachexia in vivo. Mice were allocated as non-tumour bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle control, treated with SB431542, LR3 IGF-I, SB431542 and LR3 IGF-I, or GW788388 (intraperitoneally or orally). In vitro, differentiation index and mean nuclei count increased using SB431542, GW788388, LR3 IGF-I. In vivo, GW788388 was superior to SB431542 in limiting loss of bodyweight, grip-strength and gastrocnemius weight. and downregulated Atrogin-1 expression comparable to NTB mice. LR3 IGF-I treatment limited loss of muscle mass, but at the expense of accelerated tumour growth. In conclusion, treatment with GW788388 prevented cancer cachexia, and downregulated associated ubiquitin ligase Atrogin-1.
|Persistent URL||dx.doi.org/10.1038/s41598-019-46178-9, hdl.handle.net/1765/118065|
Levolger, S, Wiemer, E.A.C, van Vugt, J.L.A, Huisman, S.A, van Vledder, M.G, van Damme-van Enge, S, … de Bruin, R.W.F. (2019). Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting. Scientific Reports, 9(1). doi:10.1038/s41598-019-46178-9