GL261 glioblastoma induces delayed body weight gain and stunted skeletal muscle growth in young mice.

Abstract

The survival rate for children and adolescents has increased to over 85%. However, there is limited understanding of the impact of pediatric cancers on muscle development and physiology. Given that brain tumors alone account for 26% of all pediatric cancers, this study aimed to investigate the skeletal muscle consequences of tumor growth in young mice. C2C12 myotubes were cocultured with GL261 murine glioblastoma cells to assess myotube size. GL261 cells were then injected subcutaneously into 4-wk-old male C57BL/6J mice. Animals were euthanized 28 days post-GL261 implantation. Muscle function was tested in vivo and ex vivo. Muscle protein synthesis was estimated via the SUnSET method, and gene/protein expression levels were assessed via Western blotting and qPCR. In vitro, the C2C12 cultures exposed to GL261 exhibited myotube atrophy, consistent with a disrupted anabolic/catabolic balance. In vivo, carcass, heart, and fat mass were significantly reduced in the tumor-bearing mice. Skeletal muscle growth was impeded in the GL261 hosts, along with a smaller muscle cross-sectional area (CSA). Both in vivo muscle torque and the ex vivo Extensor Digitorum Longus (EDL) muscle force were unchanged. At molecular level, the tumor hosts displayed reduced estimations of muscle protein synthesis and increased muscle protein ubiquitination, in disagreement with decreased muscle ubiquitin ligase mRNA expression. Overall, we showed that GL261 tumors impact the growth of pediatric mice by stunting skeletal muscle development, decreasing muscle mass, reducing muscle fiber size, diminishing muscle protein synthesis, and altering protein catabolism signaling.NEW & NOTEWORTHY This study shows that pediatric brain tumors stunt muscle development in young mice. GL261 glioblastoma cells caused myotube atrophy, reduced carcass, heart, and fat mass, and impeded skeletal muscle growth. Tumor-bearing mice had decreased muscle protein synthesis and increased protein ubiquitination. This is the first demonstration that GL261 tumors reduce muscle mass and fiber size, impair muscle function and innervation, and alter muscle protein turnover.