Abstract 19281: Tumor Susceptibility Gene 101 Positively Regulates Physiological Cardiac Hypertrophy by Promoting Endosomal Recycling of IGF-1R

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Abstract

Background: Tumor susceptibility gene 101 (Tsg101) is a ubiquitously expressed protein which plays a critical role in the endosome-mediated recycling of membrane receptors. Given that development of physiological cardiac hypertrophy has primarily been ascribed to the insulin-like growth factor-1 receptor (IGF-1R), we therefore hypothesized that Tsg101 may positively regulate physiological heart growth through facilitating the recycling of IGF-1R to the myocyte membrane.

Methods & Results: First, mice underwent high-intensity treadmill training for one week (25m/min, 1h/day) to induce physiological cardiac hypertrophy. We observed that the Tsg101 expression in treadmill-trained hearts was increased by 3-fold, compared to sedentary controls (n=9, p<0.01). Next, we generated a transgenic (TG) mouse model with cardiac-specific overexpression of Tsg101 (three TG lines: 15-, 11- and 4-fold overexpression). Mice from all three TG-lines exhibited a physiological cardiac hypertrophy, 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). Mechanistically, we identified that Tsg101 interacted with IGF-1R and Rab11-family interacting protein 3 (FIP3), which is well-known to initiate endosome recycling of membrane receptors. In vitro, adenovirus-mediated overexpression of Tsg101 in neonatal rat cardiomyocytes resulted in cell hypertrophy, which was blocked by addition of Monensin (10μM), an inhibitor of endosomal recycling, and Picropodophyllin (1μM), an inhibitor of IGF-1R signaling. Lastly, we generated an inducible cardiac-specific Tsg101 knockdown (KD) mouse model, which showed a significant inhibition of Rab11a/FIP3-mediated endosome recycling pathway, leading to the decreased levels of IGF-1R at the myocyte membrane. Consequently, Tsg101-KD mice failed to develop cardiac hypertrophy after intense treadmill training.

Conclusion: Together, these data indicate that Tsg101 could positively regulate physiological cardiac hypertrophy through facilitating the FIP3-mediated endosomal recycling of IGF-1R to the cardiomyocyte membrane.

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