Phosphate homeostasis is adjusted by local metabolism in the extracellular matrix which supplies inorganic phosphorus produced by phosphorus compounds such as the pyrophosphoric acid, besides dynamic phosphate metabolism due to dietary intake, bone metabolism and the renal handling. We previously demonstrated that the activity of ENPP1 regulated extracellular phosphate/calcium status in the soft tissue and affected locomotor functions in mice. As the lack of Enpp1 activity exhibited the impaired bone mineralization accompanying locomotor function in mice, suggesting, local phosphate metabolism directly participates bone and muscle development. We therefore investigated to clarify the role of extracellular phosphate metabolism on the function of locomotor activity in mice, especially in the energy metabolism in support of muscle function and bone tissue development.
Mice with loss of function of mutation in ENPP1 (ENPP1asj) exhibited hypophosphatemia in 6th months of age compared to wild-type (WT) littermates. The rise of serum FGF23 was observed prior to changes in serum phosphorus of ENPP1asj, it already appeared in eight-weeks old. Notably, adipose tissue mass in bone marrow cavity of tibia were increased in Enpp1asj compared to WT. These data suggested the involvement of Enpp1-mediate local phosphate metabolism in the energy metabolic pathway. In the next step, direct effect of extracellular phosphate on the energy metabolism was assessed in cultured C2C12 cells while the alteration of phosphate homeostasis in mice was recreated in culture medium containing different levels of phosphate and the antagonist of Enpp1. As results, the protein levels of glucose transporter and ATP synthase revealed with western blot analysis were decreased by a blockade of ENPP1 activity in cultured cells. These results suggested that the altering phosphate dynamics depend on Enpp1 function at cell membrane affect glucose-ATP metabolism. The phosphate homeostasis plays an essential role to control consumption of the nourishment based on the energy metabolism.