Abstract 139: Phenotypic Spectrum Caused By Transgenic Overexpression Of mTOR In The Heart.
The mammalian target of rapamycin (mTOR) plays an important role in cell growth caused by insulin/PI3-kinase signaling pathway in multiple organs including hearts. Inhibition of mTOR with rapamycin suggests that mTOR promotes cardiac hypertrophy. However, the role of mTOR in the heart remains incompletely defined because recent reports revealed the existence of a rapamycin-insensitive mTOR complex (mTORC2). We have seen enhanced mTOR activation in advanced cardiac hypertrophy in an in vivo LV pressure-overload model. To develop a model for investigating direct effects of mTOR in cardiac hypertrophy, we generated transgenic mice with cardiac-specific overexpression of wild type HA-tagged mTOR driven by the α-MHC promoter (mTOR-Tg). One of founders died with massive cardiac hypertrophy at 4wks. Two viable Tg lines (Tg4 and Tg52) were derived from independent founders. HA blotting confirmed cardiac-specific expression of the transgene in both lines. The increased expression level of mTOR protein in Tg52 was significantly higher than Tg4 [3.29±0.19 vs 2.41±0.17 fold increase compared with each litter mate control (NTg), p<0.05, n=3 each group]. Interestingly, in Tg4, a HW/BW ratio was comparable in male Tg and NTg at age 13wks [5.31±0.19 (n=10) vs 5.46±0.24 (n=12)]. In contrast, Tg52 showed significant cardiac hypertrophy [Tg vs NTg, 6.28±0.18 (n=6) vs 5.38±0.09 (n=7), p<0.05] at the same age. To study the mechanism of the different cardiac size, we examined phosphorylation of p70S6 kinase (p70S6K) and 4EBP1. Level of phosphorylated 4EBP1 (Thr37/46) in Tg52 was much higher than that seen in Tg4 (n=3 each group). On the other hand, though phosphorylation of p70S6K (Thr389) in Tg52 was increased, the level of p70S6K phosphorylation in Tg4 was almost comparable to that seen in NTg (n=3 each group). Akt (Ser473), which was recently revealed as a direct target of mTOR via mTORC2, was phosphorylated in both lines. Echocardiography was performed at age 13wks. In both lines, there were no significant functional alterations in %FS, LVDd, LVDs and HR (n=5 each group). These data suggest that
overexpression of mTOR phosphorylates the downstream molecules in the heart and
cardiac hypertrophy induced by mTOR mediats in activity-of-mTOR dependent manner.