Fig. 8.

Working model representing the proposed signaling pathways induced by vitamin D signaling in regulating skeletal muscle mass. Active vitamin D bound to vitamin D receptors maintains proteostasis by inhibiting p-Stat3 signaling and downstream C/EBP δ activity, thereby inhibiting the production of Myostatin. In fast muscles, active vitamin D additionally promotes p-Stat5 expression that could function to inhibit Stat3 expression and function. In the absence of vitamin D signaling, increased levels of Myostatin induces p-Smad3 signaling, which in turn inhibits components of the mTOR pathway, p-p70S6 kinase, and p-rpS6. Translocation of active FOXO3 into the nucleus due to reduced mTOR pathway signaling can upregulate the expression of various atrogenes. Paradoxically, autophagy regulators and targets of FOXO3 signaling, LC3b and Bnip3, display decreased expression, suggesting a block in the autophagic process and possibly an inhibition of recruitment of FOXO3 to the promoters of these genes. Additionally, active vitamin D reduces IL-6 production in slow muscles, possibly through the inhibition of the NF-kb complex that further attenuates p-Stat3 signaling