# Vitamin D Merging into Immune System-Skeletal Muscle Network: Effects on Human Health
## 3 Vitamin D Orchestrates Skeletal Muscle Integrity  
Skeletal muscle is a well-known target organ of vitamin D. In situ studies in muscle tissues documented the presence of VDR necessary for vitamin D uptake by myocytes, as confirmed in VDR knockout (VDRKO) mice and in humans carrying VDR natural mutations [36; 37; 38; 39]. As from further evidence in humans and animals, vitamin D and VDR expression are necessary for muscle development, myocyte differentiation, muscular volume, and function maintenance, and physical performance [40; 41; 42]. Conversely, lower vitamin D levels and lower VDR expression associate with muscular deterioration by promoting biomolecular alterations, such as increases in oxidative stress and decline of antioxidant enzyme activity, which critically contribute to muscle atrophy [21]. Nevertheless, consistent results showing beneficial effects on the muscular mass and power after vitamin D treatment are missing and are still a matter of debate, as exhaustively summarized elsewhere [22]. In athletic and nonathletic populations, an adequate vitamin D level seems to ameliorate physical performance, likely due to hormone-induced enhancement of exercise capacity and cardiorespiratory fitness; in light of this observation, it would be conceivable to control the vitamin D status whenever physical activity is recommended as a therapeutic approach for CV risk prevention, primary or secondary to other diseases [43; 44; 45; 46]. There is evidence that vitamin D accumulates in skeletal muscle cells, which can take up [25(OH)D] from the bloodstream through the vitamin D binding protein (DBP). Thus, it seems that the skeletal muscle provides a \"functional store\" for this hormone, which could be released upon a decrease in blood concentration. Of note, the ability of the skeletal muscle to maintain vitamin D circulating levels seems to be enhanced by regular physical exercise [47]. Isolated human skeletal muscle shows specific signals for the VDR protein with a different intensity expression before and after myotube fusion, although VDR presence in human skeletal muscle was previously debated [48; 49]. In tissues, VDR is predominantly found in fast-twitch fibers, while slow muscles show lower receptor expression; regardless of muscle fiber types, a direct association between vitamin D level and intramyonuclear VDR concentration is documented [21]. Thus far, rather than hypovitaminosis D alone, the concomitant decline of circulating vitamin D and muscular VDR seems to be determinant for intracellular signaling damage and muscle function impairment. The very poor vitamin D/VDR status observed in age-related sarcopenia--a pathologic condition characterized by muscle mass reduction and function loss--or in myopathy associates with muscle decline and injury and very often contributes to the development of overlapping diseases, including dysmetabolism and diabetes [48; 50; 51; 52]. Interestingly, human  
Figure 1: Vitamin D coordinates the anti-inflammatory immune response. Vitamin D exerts anti-inflammatory effects promoting protolerogenic immune dominance polarization.  
skeletal muscle cells shortly exposed to a VDR agonist (in pulse/recovery assay) showed a rapid functional activation of the insulin (I)-dependent intracellular cascade, lasting for 12 h even in the absence of the ligand; this effect occurs simultaneously at glucose transporter type 4 (GLUT4) nuclear translocation, induced by non-genomic actions [48]. Hence, adequate vitamin D levels/VDR expression warrant muscular integrity and avoid musculoskeletal disorders in view of the multifaceted effects converging onto muscle development, mass/volume/performance maintenance, function regulation and metabolism control, therefore, largely contributing to general health homeostasis.