Giovanni E Davogustto1, Rebecca L Salazar1, Hernan G Vasquez1, Anja Karlstaedt1, William P Dillon1, Patrick H Guthrie1, Joseph R Martin1, Heidi Vitrac2, Gina De La Guardia1, Deborah Vela3, Aleix Ribas-Latre4, Corrine Baumgartner4, Kristin Eckel-Mahan4, Heinrich Taegtmeyer5. 1. Division of Cardiology, Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, USA. 2. Tosoh Bioscience LLC, King of Prussia, PA, USA. 3. Cardiovascular Pathology Research Laboratory, Texas Heart Institute at CHI St. Luke's Health, and the Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA. 4. Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA. 5. Division of Cardiology, Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address: Heinrich.Taegtmeyer@uth.tmc.edu.
Abstract
RATIONALE: The nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) and its primary inhibitor, tuberin (TSC2), are cues for the development of cardiac hypertrophy. The phenotype of mTORC1 induced hypertrophy is unknown. OBJECTIVE: To examine the impact of sustained mTORC1 activation on metabolism, function, and structure of the adult heart. METHODS AND RESULTS: We developed a mouse model of inducible, cardiac-specific sustained mTORC1 activation (mTORC1iSA) through deletion of Tsc2. Prior to hypertrophy, rates of glucose uptake and oxidation, as well as protein and enzymatic activity of glucose 6-phosphate isomerase (GPI) were decreased, while intracellular levels of glucose 6-phosphate (G6P) were increased. Subsequently, hypertrophy developed. Transcript levels of the fetal gene program and pathways of exercise-induced hypertrophy increased, while hypertrophy did not progress to heart failure. We therefore examined the hearts of wild-type mice subjected to voluntary physical activity and observed early changes in GPI, followed by hypertrophy. Rapamycin prevented these changes in both models. CONCLUSION: Activation of mTORC1 in the adult heart triggers the development of a non-specific form of hypertrophy which is preceded by changes in cardiac glucose metabolism.
RATIONALE: The nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) and its primary inhibitor, tuberin (TSC2), are cues for the development of cardiac hypertrophy. The phenotype of mTORC1 induced hypertrophy is unknown. OBJECTIVE: To examine the impact of sustained mTORC1 activation on metabolism, function, and structure of the adult heart. METHODS AND RESULTS: We developed a mouse model of inducible, cardiac-specific sustained mTORC1 activation (mTORC1iSA) through deletion of Tsc2. Prior to hypertrophy, rates of glucose uptake and oxidation, as well as protein and enzymatic activity of glucose 6-phosphate isomerase (GPI) were decreased, while intracellular levels of glucose 6-phosphate (G6P) were increased. Subsequently, hypertrophy developed. Transcript levels of the fetal gene program and pathways of exercise-induced hypertrophy increased, while hypertrophy did not progress to heart failure. We therefore examined the hearts of wild-type mice subjected to voluntary physical activity and observed early changes in GPI, followed by hypertrophy. Rapamycin prevented these changes in both models. CONCLUSION: Activation of mTORC1 in the adult heart triggers the development of a non-specific form of hypertrophy which is preceded by changes in cardiac glucose metabolism.
Authors: Yasmin S Hamirani; Bijoy K Kundu; Min Zhong; Andrew McBride; Yinlin Li; Giovanni E Davogustto; Heinrich Taegtmeyer; Jamieson M Bourque Journal: Cardiology Date: 2015-11-24 Impact factor: 1.869
Authors: Mirko Völkers; Shirin Doroudgar; Nathalie Nguyen; Mathias H Konstandin; Pearl Quijada; Shabana Din; Luis Ornelas; Donna J Thuerauf; Natalie Gude; Kilian Friedrich; Stephan Herzig; Christopher C Glembotski; Mark A Sussman Journal: EMBO Mol Med Date: 2014-01 Impact factor: 12.137
Authors: David E Harrison; Randy Strong; Zelton Dave Sharp; James F Nelson; Clinton M Astle; Kevin Flurkey; Nancy L Nadon; J Erby Wilkinson; Krystyna Frenkel; Christy S Carter; Marco Pahor; Martin A Javors; Elizabeth Fernandez; Richard A Miller Journal: Nature Date: 2009-07-08 Impact factor: 49.962