Exogenous pyruvate alleviates UV-induced hyperpigmentation via restraining dendrite outgrowth and Rac1 GTPase activity.

BACKGROUND

Melanin is synthesized in melanocytes and transferred to keratinocytes through dendrites. Endogenous pyruvate is a key metabolite for ATP production in glycolysis, and the tricarboxylic acid (TCA) cycle and exogenous pyruvate provide protection against oxidative stress and acidosis in the intercellular space. The function of pyruvate in the regulation of dendrite outgrowth remains to be elucidated.

OBJECTIVE

We examined the effect of pyruvate on dendritic elongation and skin pigmentation

METHODS

Murine B16F10 melanoma cells and human primary melanocytes were used for in vitro analysis. Melanin quantitation and histochemical staining were performed in a 3D pigmented human skin model.

RESULTS

We demonstrated the participation of monocarboxylate transporters (MCTs) responsible for the membrane transport of pyruvate in B16F10 melanoma cells. The accumulation of pyruvate occurred in a pH-dependent manner, which was highly sensitive to a specific MCT inhibitor (α-cyano-4-hydroxycinnamic acid). α-MSH-induced morphological changes, including dendrite elongation and growth-cone-like structure, were diminished in B16F10 cells upon treatment with pyruvate. In addition, the number of dendrite branches was reduced in normal human epidermal melanocytes. As the Rho-subfamily of monomeric GTP-binding proteins modulates dendrite formation, we subsequently examined the suppression of Rac1 activation by pyruvate, but not RhoA and Cdc42. Furthermore, pyruvate showed anti-melanogenic effects against UV-induced pigmentation in reconstructed pigmented epidermis, established by co-seeding autologous melanocytes and keratinocytes, which act similar to in vivo skin tissue.

CONCLUSION

These results suggest that pyruvate treatment may be an alternative or additive therapeutic strategy to prevent hyperpigmentation.