Introduction: The Src-associated in mitosis 68 kDa (Sam68) belongs to the STAR (signal transducer and activator of RNA) family of RNA-binding proteins. Our recent work revealed its critical role in the regulation of adipose thermogenesis. However, whether Sam68 regulates cardiomyocyte biology and heart disease is currently unknown. Methods and Results: Echocardiography analyses were performed in Sam68 -/- mice and WT littermates; the baseline left-ventricular wall thickness (LVPWs and LVPWd), chamber size (LVDs and LVDd), and contractility (LVEF and FS) are similar between the 2 groups of animals. However, after transverse aortic constriction (TAC) for 2 and 4 weeks, Sam68 -/- mice exhibited a significantly lesser increase in LV wall thickness (at 2 and 4 weeks), a closer to normal LV chamber size (at 4 weeks), and a lower heart-weight (HW)/body-weight (BW) ratio (at 4 weeks), as compared to WT controls. Consistently, after continuous administration of angiotensin II (by subcutaneous osmotic minipumps) for 2 weeks, Sam68 -/- mice displayed a similarly ameliorated LV wall thickness, chamber size, and HW/BW ratio. The attenuated hypertrophic responses of Sam68 -/- mice to both TAC and Ang II treatment was supported by a lowered expression of fetal genes (β-myosin heavy chain, atrial and brain natriuretic peptides) in the heart (qRT-PCR) and excitingly, by the decreased activity of mTORC1, as indicated by the lowered levels of phosphorylated S6K1 and 4E-BP1 (Western blotting). The cardiomyocyte-specific role of Sam68 was further confirmed in cultured H9c2 cells with lentivirus-mediated Sam68 knockdown, which confirmed the reduction of mTORC1 activity. Furthermore, co- immunoprecipitation assays revealed that the endogenous Sam68 protein interacts Raptor and mTOR, but not Rictor, in the mTOR complex. Experiments are underway to establish the functional significance of the Sam68-mTOR pathway in cardiac hypertrophy and failure in vivo. Conclusion: Collectively, our data suggest that Sam68 is a novel cofactor of mTORC1. It interacts with Raptor to augment mTOR signaling and contribute to the development of cardiac hypertrophy.