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The possibility to use vitamin D supplementation to improve muscle wasting, with particular focus on cancer cachexia, is discussed.Vitamin D exerts biological actions on myogenic precursor proliferation and differentiation, impinging on muscle regeneration. However, the effects of VitD supplementation in diseases associated with muscle atrophy, such as cancer cachexia, are poorly investigated. Data obtained in experimental models of cancer cachexia show that the administration of vitamin D to tumor-bearing animals is not able to prevent or delay both muscle wasting and adipose tissue depletion, despite increased expression of muscle vitamin D receptor. Not just vitamin D supplementation impairs muscle damage-induced regeneration, suggesting that upregulation of vitamin D receptor signaling could contribute to muscle wasting.Vitamin D supplementation is likely beneficial to reduce or delay aging-related sarcopenia and osteoporosis, although the available data still put in evidence significant discrepancies. By contrast, VitD supplementation to tumor-bearing animals or to rats with arthritis was shown to be totally ineffective. In this regard, the adoption of VitD treatment in patients with cancer cachexia or other chronic diseases should be carefully evaluated, in particular whenever a regenerative process might be involved.