Cardiomyocytes adapt to physical stress by increasing their size while 
maintaining cell function. The serine/threonine kinase Akt plays a critical role 
in this process of adaptation. We previously reported that transgenic 
overexpression of an active form of Akt (Akt-E40K) in mice results in increased 
cardiac contractility and cell size, as well as improved sarcoplasmic reticulum 
(SR) Ca(2+) handling. Because it is not fully elucidated, we decided to study 
the molecular mechanism by which Akt-E40K overexpression improves SR Ca(2+) 
handling. To this end, SR Ca(2+) uptake and the phosphorylation status of 
phospholamban (PLN) were evaluated in heart extracts from wild-type and Akt-E40K 
mice and mice harboring inducible and cardiac specific knock-out of 
phosphatidylinositol-dependent kinase-1, the upstream activator of Akt. 
Moreover, the effect of Akt was assessed in vitro by overexpressing a mutant Akt 
targeted preferentially to the SR, and by biochemical assays to evaluate 
potential interaction with PLN. We found that when activated, Akt interacts with 
and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase 
IIdelta site, whereas silencing Akt signaling, through the knock-out of 
phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of 
PLN at Thr(17). Furthermore, overexpression of SR-targeted Akt in cardiomyocytes 
improved Ca(2+) handling without affecting cell size. Thus, we describe here a 
new mechanism whereby the preferential translocation of Akt to the SR is 
responsible for enhancement of contractility without stimulation of hypertrophy.