1. Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy
- Author
-
Aleix Ribas-Latre, Anja Karlstaedt, Heidi Vitrac, William P. Dillon, Deborah Vela, Hernan G. Vasquez, Gina De La Guardia, Heinrich Taegtmeyer, Corrine Baumgartner, Giovannis E Davogustto, Patrick H. Guthrie, Rebecca Salazar, Joseph R Martin, and Kristin Eckel-Mahan
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Glucose uptake ,Cardiomegaly ,Mice, Transgenic ,mTORC1 ,Nutrient sensing ,Mechanistic Target of Rapamycin Complex 1 ,030204 cardiovascular system & hematology ,Carbohydrate metabolism ,Article ,Muscle hypertrophy ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Tuberous Sclerosis Complex 2 Protein ,medicine ,Animals ,Myocytes, Cardiac ,Glycolysis ,Phosphorylation ,Isomerases ,Molecular Biology ,Cells, Cultured ,Sirolimus ,business.industry ,medicine.disease ,Diet ,Enzyme Activation ,Mice, Inbred C57BL ,Disease Models, Animal ,Glucose ,030104 developmental biology ,Endocrinology ,Gene Knockdown Techniques ,Heart failure ,Glucose-6-Phosphatase ,biological phenomena, cell phenomena, and immunity ,TSC2 ,Cardiology and Cardiovascular Medicine ,business ,Oxidation-Reduction ,Signal Transduction - 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.
- Published
- 2021
- Full Text
- View/download PDF