mTOR pathway and Ca²⁺ stores mobilization in aged smooth muscle cells

Abstract

Aging is considered to be driven by the so called senescence pathways, especially the mTOR route, although there is almost no information on its activity in aged tissues. Aging also induces Ca²⁺ signal alterations, but information regarding the mechanisms for these changes is almost inexistent. We investigated the possible involvement of the mTOR pathway in the age-dependent changes on Ca²⁺ stores mobilization in colonic smooth muscle cells of young (4 month old) and aged (24 month old) guinea pigs. mTORC1 activity was enhanced in aged smooth muscle, as revealed by phosphorylation of mTOR and its direct substrates S6K1 and 4E-BP1. Mobilization of intracellular Ca²⁺ stores through IP₃R or RyR channels was impaired in aged cells, and it was facilitated by mTOR and by FKBP12, as indicated by the inhibitory effects of KU0063794 (a direct mTOR inhibitor), rapamycin (a FKBP12-mediated mTOR inhibitor) and FK506 (an FKBP12 binding immunosuppressant). Aging suppressed the facilitation of the Ca²⁺ mobilization by FKBP12 but not by mTOR, without changing the total expression of FKBP12 protein. In conclusion, or study shows that in smooth muscle aging enhances the constitutive activity of mTORC1 pathway and impairs Ca²⁺ stores mobilization by suppression of the FKBP12-induced facilitation of Ca²⁺ release.