PMID- 30884248 OWN - NLM STAT- MEDLINE DCOM- 20200619 LR - 20210210 IS - 1530-6860 (Electronic) IS - 0892-6638 (Print) IS - 0892-6638 (Linking) VI - 33 IP - 6 DP - 2019 Jun TI - Tsg101 positively regulates physiologic-like cardiac hypertrophy through FIP3-mediated endosomal recycling of IGF-1R. PG - 7451-7466 LID - 10.1096/fj.201802338RR [doi] AB - Development of physiologic cardiac hypertrophy has primarily been ascribed to the IGF-1 and its receptor, IGF-1 receptor (IGF-1R), and subsequent activation of the protein kinase B (Akt) pathway. However, regulation of endosome-mediated recycling and degradation of IGF-1R during physiologic hypertrophy has not been investigated. In a physiologic hypertrophy model of treadmill-exercised 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-specific overexpression of Tsg101. These TG mice exhibited a physiologic-like cardiac hypertrophy phenotype at 8 wk evidenced by: 1) the absence of cardiac fibrosis, 2) significant improvement of cardiac function, and 3) increased total and plasma membrane levels of IGF-1R and increased phosphorylation of Akt. Mechanistically, we identified that Tsg101 interacted with family-interacting protein 3 (FIP3) and IGF-1R, thereby stabilizing FIP3 and enhancing recycling of IGF-1R. In vitro, adenovirus-mediated overexpression of Tsg101 in neonatal rat cardiomyocytes resulted in cell hypertrophy, which was blocked by addition of monensin, an inhibitor of endosome-mediated recycling, and by small interfering RNA-mediated knockdown (KD) of FIP3. Furthermore, cardiac-specific KD of Tsg101 showed a significant reduction in levels of endosomal recycling compartment members (Rab11a and FIP3), IGF-1R, and Akt phosphorylation. Most interestingly, Tsg101-KD 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-mediated endosomal recycling of IGF-1R.-Essandoh, K., Deng, S., Wang, X., Jiang, M., Mu, X., Peng, J., Li, Y., Peng, T., Wagner, K.-U., Rubinstein, J., Fan, G.-C. Tsg101 positively regulates physiologic-like cardiac hypertrophy through FIP3-mediated endosomal recycling of IGF-1R. FAU - Essandoh, Kobina AU - Essandoh K AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. FAU - Deng, Shan AU - Deng S AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. AD - Department of Cardiology, Union Hospital-Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Wang, Xiaohong AU - Wang X AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. FAU - Jiang, Min AU - Jiang M AD - Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, USA. FAU - Mu, Xingjiang AU - Mu X AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. FAU - Peng, Jiangtong AU - Peng J AD - Department of Cardiology, Union Hospital-Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Li, Yutian AU - Li Y AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. FAU - Peng, Tianqing AU - Peng T AD - Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada. FAU - Wagner, Kay-Uwe AU - Wagner KU AD - Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA. FAU - Rubinstein, Jack AU - Rubinstein J AD - Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, USA. FAU - Fan, Guo-Chang AU - Fan GC AD - Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. LA - eng GR - R01 GM112930/GM/NIGMS NIH HHS/United States GR - R01 GM126061/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190318 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (DNA-Binding Proteins) RN - 0 (Endosomal Sorting Complexes Required for Transport) RN - 0 (Transcription Factors) RN - 0 (Tsg101 protein) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.11.10 (I-kappa B Kinase) SB - IM MH - Animals MH - Cardiomegaly/*physiopathology MH - DNA-Binding Proteins/*physiology MH - Endosomal Sorting Complexes Required for Transport/*physiology MH - Endosomes/*metabolism MH - Female MH - Gene Expression Profiling MH - I-kappa B Kinase/*physiology MH - Male MH - Mice MH - Rats MH - Receptor, IGF Type 1/*metabolism MH - Transcription Factors/*physiology PMC - PMC6529337 OTO - NOTNLM OT - Rab11-FIP3 OT - cardiac remodeling OT - endosomes OT - exercise training OT - membrane receptor COIS- This study was supported partially by U.S. National Institutes of Health, National Institute of General Medical Sciences Grants R01 GM-112930 and GM-126061, American Heart Association (AHA) Established Investigator Award 17EIA33400063 (to G.-C.F.), and AHA Predoctoral Fellowship 18PRE34030123 (to K.E.). The authors declare no conflicts of interest. EDAT- 2019/03/19 06:00 MHDA- 2020/06/20 06:00 PMCR- 2020/03/18 CRDT- 2019/03/19 06:00 PHST- 2019/03/19 06:00 [pubmed] PHST- 2020/06/20 06:00 [medline] PHST- 2019/03/19 06:00 [entrez] PHST- 2020/03/18 00:00 [pmc-release] AID - FJ_201802338RR [pii] AID - 10.1096/fj.201802338RR [doi] PST - ppublish SO - FASEB J. 2019 Jun;33(6):7451-7466. doi: 10.1096/fj.201802338RR. Epub 2019 Mar 18.