Vitamin D stimulates Il-15 synthesis in rodent muscle

TL;DR

This study shows that vitamin D increases the production of a muscle protein called IL-15, which is important for muscle and immune function.

Contribution

The study identifies vitamin D as a novel regulator of IL-15 synthesis in skeletal muscle, mediated by the vitamin D receptor.

Findings

Vitamin D3 metabolites increase Il-15 gene expression in a dose-dependent manner in C2C12 myotubes.

Muscle Il-15 mRNA is elevated in rats treated with 1,25(OH)2D3.

Vitamin D receptor is essential for the regulation of muscle Il-15 by vitamin D.

Abstract

Besides its classical skeletal function, vitamin D plays a critical role in both skeletal muscle and the immune system. Interleukin-15 (IL-15), which is highly expressed, and secreted complexed with its receptor, IL-15Rα, by skeletal muscle, stimulates the development of immune cells and affects myogenesis and muscle mass. However, little is known about possible regulators of this myokine. To test whether vitamin D could be a regulator of muscle IL-15 and IL-15Rα expression, C2C12 myotubes were treated with vitamin D3 metabolites and analysis were performed in gastrocnemius muscles of rats treated with a single intraperitoneal dose of 1,25(OH)2D3. The role of VDR was investigated by siRNA technique in C2C12 myotubes and in gastrocnemius muscles of vitamin D receptor knockout (Vdr-KO) mice. Treatment of C2C12 myotubes with 1,25(OH)2D3 or 25(OH)D3 increased Il-15 gene expression in a dose-dependent manner and 1,25(OH)2D3 also moderately increased the relative Il-15 protein amount. Rats treated with a single dose of 1,25(OH)2D3 demonstrated a higher mRNA abundance of muscle Il-15 than controls. The 1,25(OH)2D3 effect on Il-15 was considerably weaker in C2C12 myotubes treated with Vdr-specific siRNA. Vdr-KO mice showed significantly lower muscle Il-15 mRNA than WT mice. Il-15Ra mRNA and Il-15/Il-15Rα protein abundance were unaffected by 1,25(OH)2D3-treatment or VDR functionality, and Cyp27b1 activity is not required for 25(OH)D3-mediated Il-15 gene expression.

The results provide evidence for a regulatory role of hydroxyvitamin D3 metabolites on the Il-15 synthesis in skeletal muscle cells, which is largely mediated by the VDR.

•Dose-dependent Il-15 mRNA increase in C2C12 myotubes by 1,25(OH)2D3 or 25(OH)D3 treatment.•1,25(OH)2D3 moderately increases the relative Il-15 protein amount in C2C12 myotubes.•1,25(OH)2D3 moderately increases the muscular Il-15 mRNA in vivo.•1,25(OH)2D3-mediated regulation of muscle Il-15 mRNA depends on the VDR.•Reduced muscle Il-15 mRNA abundance in Vdr-KO mice compared to WT mice.

Dose-dependent Il-15 mRNA increase in C2C12 myotubes by 1,25(OH)2D3 or 25(OH)D3 treatment.

1,25(OH)2D3 moderately increases the relative Il-15 protein amount in C2C12 myotubes.

1,25(OH)2D3 moderately increases the muscular Il-15 mRNA in vivo.

1,25(OH)2D3-mediated regulation of muscle Il-15 mRNA depends on the VDR.

Reduced muscle Il-15 mRNA abundance in Vdr-KO mice compared to WT mice.

Figures