Abstract
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.
Highlights
Progressive skeletal muscle wasting, with or without loss of adipose tissue, is observed in up to 50 per cent of all cancer patients[1,2]
We investigated the efficacy of ALK4/5 inhibitors SB431542 and GW788388, and the insulin-like growth factor-I (IGF-I) analogue LONG R3 IGF-I, in vitro using the C2C12 skeletal muscle cell model
C2C12 myoblasts were cultured in differentiation medium (DM) supplemented with ALK4/5 inhibitors SB431542 (Fig. 1A), or GW788388 (Fig. 1B) during six days
Summary
Progressive skeletal muscle wasting, with or without loss of adipose tissue, is observed in up to 50 per cent of all cancer patients[1,2]. Supplementation of insulin-like growth factors attenuates muscle wasting in experimental cancer cachexia models[48,49] Taking these data into consideration, we sought to determine whether (1) systemic inhibition of ALK4/5, and potentially blocking the myostatin signalling pathway, enhances myogenesis in vitro and limits muscle wasting in experimental cancer cachexia in vivo, and (2) whether combined treatment of ALK 4/5 inhibition and IGF-I supplementation would improve treatment outcome without impacting on tumour growth[50]. Our data shows that both ALK4/5 receptor inhibition and LONG R3 IGF-I analogues enhance C2C12 skeletal muscle cell differentiation in vitro, successfully limit cancer cachexia in vivo, and down-regulates the associated target genes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
