Tsg101 Regulates Rab11FIP3‐Mediated Endosomal Recycling of IGF‐1R in Physiological Cardiac Hypertrophy

Abstract

BackgroundDevelopment of physiological cardiac hypertrophy has primarily been ascribed to the insulin‐like growth factor 1 (IGF‐1) and its receptor, IGF‐1R and subsequent activation of the Akt pathway. Previous studies have demonstrated the effects of IGF‐1 on both pathological and physiological remodeling whereas IGF‐1R has consistently been linked to only physiological heart growth. Thus, the balance between de novo synthesis and recycling or degradation of IGF‐1R through the endosomal system is critical for physiological heart growth. However, regulation of endosome‐mediated recycling and degradation of IGF‐1R during physiological hypertrophy has not been investigated.Methods & ResultsIn the current study, we sought to determine the role of endosome‐mediated recycling and degradation of IGF‐1R on physiological cardiac hypertrophy. Male FVB/n mice (7–8 weeks old) underwent intense treadmill exercise training for 1 week to induce physiological hypertrophy. We observed that mediators of recycling (Rab11a, Rab11FIP3) and degradation (Rab7) of endosomes were enhanced in exercise‐trained mice. Of importance, levels of tumor susceptibility gene 101 (Tsg101), a key member of the Endosomal Sorting Complex required for Transport (ESCRT), were dramatically elevated in hearts of exercise‐trained mice, compared to controls (n=9, p<0.01). To determine the role of Tsg101 on physiological hypertrophy, we generated a transgenic mice model with cardiac‐specific overexpression of Tsg101. These transgenic mice exhibited a physiological hypertrophy‐like phenotype at 8 weeks, evidenced by the absence of cardiac fibrosis, significant improvement of cardiac function, increased total and plasma membrane levels of IGF‐1R and increased phosphorylation of Akt. Mechanistically, we identified that Tsg101 interacted with IGF‐1R and Rab11FIP3, which constitutively binds to Rab11a at endosomal recycling compartments to initiate recycling of endosomes. In vitro, adenovirus‐mediated overexpression of Tsg101 in neonatal rat cardiomyocytes resulted in increased cardiomyocyte size, which was blocked by addition of monensin, an inhibitor of Rab11/FIP3‐endosome recycling. Furthermore, cardiac‐specific knockdown of Tsg101 showed a significant reduction in levels of Rab11a, Rab11FIP3, IGF‐1R and Akt phosphorylation. Most interestingly, Tsg101‐knockdown mice failed to develop cardiac hypertrophy after intense treadmill training.ConclusionOur data identify Tsg101 as a novel regulator of physiological cardiac hypertrophy through facilitating the Rab11FIP3‐mediated endosomal recycling of IGF‐1R.Support or Funding InformationNIH 2R01HL‐087861