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Vitamin D (VD) deficiency is associated with impairment of muscle mass and performance and is highly prevalent in cachectic patients; therefore, VD supplementation has been proposed to counteract cancer cachexia\u2010associated muscle loss. However, in both cachectic cancer patients and tumour\u2010bearing animals, VD supplementation led to disappointing results, urging the need for a better understanding of VD activity on skeletal muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cancer\u2010associated muscle wasting was reproduced in vitro by treating C2C12 myotubes with cancer cell conditioned medium, a combination of TNF\u2010\u03b1 and IFN\u03b3 or IL\u20106 pro\u2010cachectic cytokines. The biological effects and mechanisms of action of 1,25\u2010dihydroxy VD (1,25 VD) and its precursor 25\u2010hydroxy VD (25 VD) on myotubes were explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated that only 25 VD was able to protect from atrophy by activating Akt signalling, inducing protein synthesis, and stimulating the autophagic flux, while 1,25 VD had an atrophic activity per se, increasing FoxO3 levels, inducing the expression of atrogenes, and blocking the autophagic flux. Furthermore, we showed that the contrasting activities of these VD metabolites on C2C12 myotubes depend on a differential induction of VD\u201024\u2010hydroxylase and transformation of VD metabolites in pro\u2010atrophic 24\u2010hydroxylated products, as silencing of VD\u201024\u2010hydroxylase reduced the atrophic activity of 1,25 VD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Altogether these data might explain the lack of efficacy of VD treatment in vivo for the protection of muscle mass in cancer.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13269","type":"journal-article","created":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T05:55:18Z","timestamp":1551765318000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Opposing effects of 25\u2010hydroxy\u2010 and 1\u03b1,25\u2010dihydroxy\u2010vitamin D<sub>3<\/sub> on pro\u2010cachectic cytokine\u2010and cancer conditioned medium\u2010induced atrophy in C2C12 myotubes"],"prefix":"10.1111","volume":"226","author":[{"given":"Hana","family":"Sustova","sequence":"first","affiliation":[{"name":"Department of Translational Medicine University of Piemonte Orientale Novara Italy"},{"name":"Istituto Interuniversitario di Miologia (IIM)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilisa","family":"De Feudis","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine University of Piemonte Orientale Novara Italy"},{"name":"Istituto Interuniversitario di Miologia (IIM)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Reano","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine University of Piemonte Orientale Novara Italy"},{"name":"Istituto Interuniversitario di Miologia (IIM)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maraiza","family":"Alves 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