# Vitamin D Merging into Immune System-Skeletal Muscle Network: Effects on Human Health
## 4 Skeletal Muscle-Immune System Interplay: A Two-Way Route
### Skeletal Muscle Regulation of the Immune Function  
For a long time, the immune system-muscle interplay has been thought to be unilateral. The concept that the skeletal muscle can act as a fine regulator of immune function is relatively new and enhances the complexity of this interplay. One of the first evidence comes from the observation that subjects with compromised skeletal muscle show an impaired immune response to pathogens, as clearly documented by the increased risk of infections in elderly subjects affected by sarcopenia. This condition, in fact, is associated with a higher risk of developing nosocomial infections or community-acquired pneumonia and mortality [66; 67; 68], besides disability and disability-related injuries (i.e., consequent to falls). Another interesting example comes from the observation of the higher risk of infection in healthy athletes undergoing skeletal muscle exhaustion for overtraining or muscular work overloading, i.e., elite athletes experiencing regular intense endurance training, as well summarized in dedicated reports [69; 70; 71]. Conversely, it has been suggested that balanced and well-scheduled physical activity could help in maintaining a correct immune response [70]. The concept that the muscle and the immune system could dialogue in a bidirectional way essentially relies on the renewed concept that the skeletal muscle does not serve only as pure locomotor organ, dedicated exclusively to sustain body and glucose homeostasis, but, remarkably, it behaves as a proper secretory organ with exquisite immune-regulatory and anti-inflammatory functions [72]. Paradoxically, this renewed concept mostly derives from studies aimed at verifying the muscular damage induced by the exercise itself, seen as potentially harmful a tissue stress factor. In fact, it is undeniable that high intensity or aerobic exercise can induce cellular and biomolecular modifications similar to a proper inflammatory response. However, all those \"inflammatory-like\" changes are transiently activated, shortly tapered-off after exercise, and occur in association with little immune cell infiltration [70]. In fact, regular exercising and gradual exercise adaptation induce the skeletal muscle to produce and release a plethora of immune-active factors with important beneficial regulatory functions, exerted both nearby and at a distance, as addressed in the following paragraph [72]. Indeed, myocytes could control and regulate immune function through cell-to-cell interactions (especially T cells-myocytes, as addressed above), membrane surface modulatory molecules present on skeletal muscle fibers, and soluble factors, in particular, cytokines, chemokines, and growth factors. Of note, skeletal muscle cells are, nowadays, regarded as non-professional APCs, able to present antigens through major histocompatibility complex (MHC) I and II, to produce immune biomolecules that, in turn, could shape the immune response. A detailed description of those processes is exhaustively reported in the literature [61; 65]. This review would rather prefer to drive the attention on vitamin D interference at the signaling intersection between the immune system and skeletal muscle-derived cytokines (myokines).