Sexual dimorphism of mTORC2 activation in response to rapamycin <i>in vivo</i>.

<p>Male and female C57Bl/6J mice were treated with rapamycin (“low concentration” 1.5 mg/kg, administered i.p. every third day) or vehicle (control) for 42 days (n = 6-8/group). mTORC2 activity was assessed by assessment of Akt phosphorylation at S473 and its nuclear localization. A, representative western blots are shown for Akt-pS473, Akt and GAPDH of mice treated as described above. B shows results from quantitative analysis of western blots for Akt-pS473 normalized to Akt (mean ± SEM; * p < 0.035) from female and male mouse hearts. C, Immunostaining for Akt-pS473 of male and female cardiac tissue sections treated with either vehicle (control) or rapamycin for 42 days and D, quantification of % cardiomyocyte nuclei stained for Akt-pS743 (mean ± SEM; *** p < 0.0001). Male mice had lower basal mTORC2 activity, yet responded to rapamycin with an increase in phosphorylation of Akt at S473, associated with increased nuclear localization important for induction of cardioprotective mechanisms. In contrast, female mice responded to rapamycin with reduced phosphorylation of Akt at S473 and loss of cardioprotective nuclear Akt.