Cholecalciferol (vitamin D3) has a direct protective activity in C2C12 myotubes

Skeletal muscle depletion occurs, among other conditions, in oncologic patients. Cancer cachexia is a multicomponent syndrome which physiopathology involves metabolic alterations, like hormonal imbalance. One of the hormones that are dysregulated in cancer cachexia is Vitamin D (VD). Besides its important role in bone mineralization, regulating calcium and phosphate homeostasis, VD affects skeletal muscle. In fact, VD deficiency has been associated with a wide range of muscle disorders, such as a decrease in muscle mass and functionality. Even though VD deficiency is highly prevalent among advanced cancer patients with cachexia, the administration of VD in these subjects showed inconclusive results, with VD supplementation being ineffective to prevent muscle wasting in both cachectic patients and tumor-bearing animals. We show how different VD metabolites trigger contrasting effects on skeletal muscle in vitro, depending on the sites of hydroxylation or doses, thus explaining the limitations of VD-based therapy in vivo, once VD systems of biosynthesis and catabolism are dysregulated in cancer. We find that also cholecalciferol (VD3), the non-hydroxylated upstream VD metabolite, has a direct effect on muscle cells. This finding might help to make future progress in developing VD analogs with a restricted capacity to undergo hydroxylation. Then overcoming the limitations of VD supplementation in cancer-related cachexia.