Oxytocin treatment reduces cancer cachexia in a pre-clinical model

Oxytocin (OT) is a neurohypophyseal peptide with decreased expression during aging, essential for skeletal muscle homeostasis, and counteracts sarcopenia in aged mice. Yet, its function in cancer cachexia remains unexplored. We investigated OT serum levels in cancer patients, comparing these with cachectic patients and non-cancer controls, as well as OT/OT-receptor (OTR) mRNA in sarcopenic muscle. Potential benefits of OT were assessed in vitro using L6C5 myoblasts and murine isolated myofibers exposed to C26-conditioned medium and in vivo using the C26/Balb/c cancer cachexia model. Finally, the molecular effects of OT on de novo protein synthesis via bio-orthogonal non-canonical amino acid tagging (BONCAT) were investigated using MetRS^L274G C57BL/6 mice. Circulating OT was significantly lower in cancer patients than in non-cancer disease (-60 %, p < 0.01). Sarcopenic muscle showed over threefold downregulation of the OTR (p < 0.032). In vitro, OT reversed the myogenic inhibition induced by tumor cell-conditioned medium, boosting fusion index (>6-fold, p < 0.001), nuclei per myotube (>8-fold, p < 0.001), and myotube diameter (>6-fold, p < 0.001). In C26 tumor-bearing mice, OT restored skeletal muscle mass (>1.5-fold, p < 0.001), fiber cross-sectional area (>1.5-fold, p < 0.001), and overall body weight, while reducing the muscle degradation determinants: MuRF1 (>8-fold, p < 0.001) and Atrogin1 (>6-fold, p < 0.001). Metabolic proteomics showed that cancer perturbed and OT restored the synthesis of key proteins (+23 %, p < 0.05) that play essential roles in muscle regeneration and inter-organ communication. Given that OT is approved for clinical use, our findings suggest that it could quickly be translated into effective therapies for preventing or treating cachexia in cancer patients.