Abstracts

Abstract

Introduction: Up to 80% of adult cancer patients will develop involuntary body weight loss associated with skeletal muscle wasting, which altogether lead to increased morbidity and mortality. However, there is minimal understanding or research on the influence of paediatric cancers on muscle development and physiology. Given that brain tumours alone are responsible for 1/4 of all paediatric cancers, the aim of the current research was to investigate the skeletal muscle consequences associated with growth of these tumours in young mice. Methods: In vitro atrophy was assessed by co-culturing C2C12 myotubes with GL261 murine glioblastoma cells. GL261 cells (1.0 × 106) were injected subcutaneously into 4week-old male C57BL/6J mice. Body mass was monitored daily. Vehicle (n = 5) and experimental mice (n = 14) were culled 28 days after GL261 implantation. Skeletal muscle and organ weights were measured at the completion of the study. Muscle cross sectional area (CSA) was assessed via immunofluorescent stain of dystrophin. In vivo and ex vivo muscle function testing was completed at baseline and prior to completion of the study. Muscle protein synthesis was measured via the SUnSET method, and gene expression via qPCR. Results: C2C12 cells exposed to GL261 exhibited myotube atrophy. Carcass, heart, and fat mass were mitigated (P < 0.05) in the tumour bearers, whereas growth of skeletal muscles (tibialis anterior and quadriceps) was impeded in the GL261 hosts (P < 0.05), in line with significantly lower muscle fibre cross sectional (P < 0.05). In vivo gastrocnemius torque was not significantly different between groups, while the ex vivo EDL muscle force was reduced in the GL261 hosts (P < 0.05). Tumour hosts displayed reduced muscle protein synthesis (P < 0.05). MuRF-1, MUSA1 and Atrogin1 muscle ubiquitin ligase mRNA expression was lower in the GL261 hosts. Conclusions: Our research highlights the impact of GL261 glioblastoma on paediatric mice. GL261 hosts yielded a stunted development of skeletal muscle, as evidenced by de-creased skeletal muscle mass, smaller muscle fibre CSA, diminished muscle protein synthesis, and reduced cell signalling associated with protein catabolism. Future research should focus on the mechanisms responsible for the systemic long-term effects of cancer in paediatric patients and investigate potential therapeutic targets to mitigate the blunted muscle development.