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However, regulation of endosome\u2010mediated recycling and degradation of IGF\u20101R during physiologic hypertrophy has not been investigated. In a physiologic hypertrophy model of treadmill\u2010exercised mice, we observed that levels of tumor susceptibility gene 101 (Tsg101), a key member of the endosomal sorting complex required for transport, were dramatically elevated in the heart compared with sedentary controls. To determine the role of Tsg101 on physiologic hypertrophy, we generated a transgenic (TG) mouse model with cardiac\u2010specific overexpression of Tsg101. These TG mice exhibited a physiologic\u2010like cardiac hypertrophy phenotype at 8 wk evidenced by:\n                    <jats:italic>1<\/jats:italic>\n                    ) the absence of cardiac fibrosis,\n                    <jats:italic>2<\/jats:italic>\n                    ) significant improvement of cardiac function, and\n                    <jats:italic>3<\/jats:italic>\n                    ) increased total and plasma membrane levels of IGF\u20101R and increased phosphorylation of Akt. Mechanistically, we identified that Tsg101 interacted with family\u2010interacting protein 3 (FIP3) and IGF\u20101R, thereby stabilizing FIP3 and enhancing recycling of IGF\u20101R.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , adenovirus\u2010mediated overexpression of Tsg101 in neonatal rat cardiomyocytes resulted in cell hypertrophy, which was blocked by addition of monensin, an inhibitor of endosome\u2010mediated recycling, and by small interfering RNA\u2014mediated knockdown (KD) of FIP3. Furthermore, cardiac\u2010specific KD of Tsg101 showed a significant reduction in levels of endosomal recycling compartment members (Rabila and FIP3), IGF\u20101R, and Akt phosphorylation. Most interestingly, Tsg101\u2010KD mice failed to develop cardiac hypertrophy after intense treadmill training. Taken together, our data identify Tsg101 as a novel positive regulator of physiologic cardiac hypertrophy through facilitating the FIP3\u2010mediated endosomal recycling of IGF\u20101R.\u2014Essandoh, K., Deng, S., Wang, X., Jiang, M., Mu, X., Peng, J., Li, Y., Peng, T., Wagner, K.\u2010U., Rubinstein, J., Fan, G.\u2010C. Tsg101 positively regulates physiologic\u2010like cardiac hypertrophy through FIP3\u2010mediated endosomal recycling of IGF\u20101R. FASEB J. 33, 7451\u20137466 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201802338rr","type":"journal-article","created":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T19:56:41Z","timestamp":1552939001000},"page":"7451-7466","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Tsg101 positively regulates physiologic\u2010like cardiac hypertrophy through FIP3\u2010mediated endosomal recycling of IGF\u20101R"],"prefix":"10.1096","volume":"33","author":[{"given":"Kobina","family":"Essandoh","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Systems Physiology University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shan","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Systems Physiology University of Cincinnati College of Medicine Cincinnati Ohio USA"},{"name":"Department of Cardiology Union Hospital\u2010Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Systems Physiology University of Cincinnati College of Medicine Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Health and Disease Department of Internal Medicine University of Cincinnati Cincinnati Ohio 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