Vincristine impairs musculoskeletal development in pediatric mice.

BACKGROUND: Over 85% of children diagnosed with cancer now survive their disease, yet cancer and chemotherapy frequently associate with long-term health complications, including impaired musculoskeletal development. Despite high survival rates, there is limited research on how pediatric chemotherapy affects muscle and bone physiology. Vincristine, a vinca alkaloid chemotherapeutic, is widely used in pediatric oncology, but its systemic effects on the developing musculoskeletal system remain poorly understood. This study aimed to investigate the musculoskeletal consequences of vincristine in a pediatric mouse model. METHODS: Four-week-old male C57BL/6J mice were administered vincristine (1.5 mg/kg, intraperitoneally, twice weekly) or vehicle for five weeks. Body mass was monitored daily. At study endpoint (day 35), skeletal muscle mass and ex vivo extensor digitorum longus (EDL) muscle function were assessed. Trabecular and cortical bone microarchitecture were evaluated via micro-computed tomography (µCT). Molecular markers of muscle atrophy and mitochondrial function were analyzed using qPCR and western blotting. RESULTS: Vincristine-treated mice exhibited significantly reduced body mass (- 29%, p < 0.05), skeletal muscle mass (quadriceps - 39%, tibialis anterior - 33%, gastrocnemius - 25%, p < 0.05), and ex vivo EDL muscle force (- 28%, p < 0.05). Muscle fiber cross-sectional area was reduced (- 22%, p < 0.05), and SDH staining revealed a shift from oxidative to glycolytic fibers. Molecular analyses showed increased phosphorylation of STAT3Tyr705 (+ 267%, p < 0.05), no changes in the phosphorylation of AKTSer473 (p < 0.05), elevated expression of Atrogin-1 (+ 105%, p < 0.05) and MUSA1 (+ 122%, p < 0.05), and decreased PGC-1α expression (- 44%, p < 0.05), overall suggesting enhanced protein degradation and mitochondrial dysfunction. The µCT analysis revealed significant trabecular bone loss (BV/TV - 84%, Tb.Th - 18%, Tb.N - 52%, Conn.D - 89%, p < 0.05) and cortical thinning (Ct.Th - 21%, p < 0.05). Plasma CTX-1 levels were significantly higher (+ 51%, p < 0.05) in the vincristine-treated mice, indicating increased bone resorption. CONCLUSIONS: Vincristine impairs musculoskeletal development in pediatric mice, leading to muscle atrophy, muscle mitochondrial dysfunction, and bone loss. Altogether, these findings underscore the need for further research into the long-term systemic effects of this frequently prescribed pediatric anticancer agent and the development of interventions to preserve musculoskeletal health in childhood cancer survivors.