Tsg101 positively regulates physiologic-like cardiac hypertrophy through FIP3-mediated endosomal recycling of IGF-1R

What is it about?

It is well recognized that exercise training could induce physiological cardiac hypertrophy. However, the underlying mechanisms remain obscure. In this study, we observed that the expression profile of endosome-associated genes was significantly dys-regulated, especially, tumor susceptibility gene 101 (Tsg101) was the most upregulated gene in treadmill-trained mouse hearts. To further examine the significance of Tsg101 in exercise training-induced physiological cardiac hypertrophy, we generated heart-specific Tsg101-overexpressing mouse model. Interestingly, these Tsg101-overexpressing mice exhibited enlarged heart and enhanced cardiac function without cardiac fibrosis, features of physiological cardiac hypertrophy but not pathological remodeling. Similar results were achieved in vitro, where adenovirus-mediated overexpression of Tsg101 in neonatal rat cardiomyocytes resulted in increased cell size. Mechanistically, we identified that Tsg101 interacted with FIP3 and IGF-1R, thereby stabilizing FIP3 and enhancing recycling of IGF-1R. Finally, we also found that mice with cardiac-specific knockdown of Tsg101 were resistant to exercise-induced cardiac hypertrophy and showed decreased recycling of IGF-1R. In conclusion, our study elucidates a previously unrecognized role of Tsg101 in positively regulating physiological cardiac hypertrophy. This study may help us better understand the role of endosomal recycling in physiological cardiac remodeling and therefore, provide new strategies for the treatment of heart disease.

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