Abstract 15771: Tumor Susceptibility Gene 101 Promotes Physiological Cardiac Growth and Attenuates Pathological Cardiac Remodeling.

Introduction: Tumor susceptibility gene 101 (Tsg101), a key member of the endosomal sorting complex required for transport (ESCRT), plays a significant role in endosome-mediated recycling of membrane receptors. Considering that the insulin-like growth factor-1 receptor (IGF-1R) has been shown to be critical for physiological cardiac hypertrophy, it would be of great interest to investigate whether Tsg101-mediated endosome recycling contributed to IGF-1R signaling and physiological heart growth. Hypothesis: Tsg101 regulates physiological cardiac hypertrophy through endosomal recycling of IGF-1R. Methods & Results: Mice were subjected to high-intensity treadmill training for one week (25m/min, 1h/day) to induce a physiological cardiac hypertrophy. Western blot analysis revealed that the expression level of Tsg101 in treadmill-trained hearts was increased by 3-fold, compared to sedentary controls (n=9, p <0.01). Then, we generated a transgenic (TG) mouse model with cardiac-specific overexpression of Tsg101 (two TG lines: 11- and 4-fold overexpression). Both TG-lines exhibited a physiological cardiac hypertrophy-like phenotype, as evidenced by: 1) the higher ratio of heart/body weight without cardiac fibrosis, 2) enhanced cardiac function, and 3) increased myocyte membrane levels of IGF-1R, compared to wild-type controls (n=6-8, p <0.05). Co-immunoprecipitation analysis and size exclusion chromatography showed that Tsg101 existed in a complex with IGF-1R and Rab11-family interacting protein 3 (FIP3), a well-known initiator of endosome recycling of membrane receptors. In addition, we generated an inducible cardiac-specific Tsg101 knockdown (KD) mouse model, which failed to develop cardiac hypertrophy after intense treadmill training. Lastly, Tsg101-TG mice were resistant to cardiac dysfunction and fibrosis induced by the pathological hypertrophy model of transverse aortic constriction (TAC) surgery. Conclusion: Together, these data identify Tsg101 as a novel regulator of endosomal mediated recycling of IGF-1R and physiological cardiac hypertrophy and is cardio-protective against pathological cardiac remodeling. [ABSTRACT FROM AUTHOR]