Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy

• Published in: Journal of molecular and cellular cardiology Vol. 158; pp. 115 - 127
• Main Authors: Davogustto, Giovanni E., Salazar, Rebecca L., Vasquez, Hernan G., Karlstaedt, Anja, Dillon, William P., Guthrie, Patrick H., Martin, Joseph R., Vitrac, Heidi, De La Guardia, Gina, Vela, Deborah, Ribas-Latre, Aleix, Baumgartner, Corrine, Eckel-Mahan, Kristin, Taegtmeyer, Heinrich
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2021
• Subjects: Animals; Cardiomegaly - diet therapy; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - prevention & control; Cells, Cultured; Diet - methods; Disease Models, Animal; Enzyme Activation - genetics; Exercise; Gene Knockdown Techniques - methods; Glucose - metabolism; Glucose-6-Phosphatase - metabolism; Glycolysis; Hypertrophy; Isomerases - metabolism; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; mTORC1; Myocytes, Cardiac - metabolism; Oxidation-Reduction; Phosphorylation - genetics; Signal Transduction - genetics; Sirolimus - administration & dosage; Tuberous Sclerosis Complex 2 Protein - genetics; Tuberous Sclerosis Complex 2 Protein - metabolism; Glycolysis; Exercise; Metabolism; mTORC1; Hypertrophy
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2021.05.016

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. To examine the impact of sustained mTORC1 activation on metabolism, function, and structure of the adult heart. 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. 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. [Display omitted] •mTORC1 activation via inducible cardiac-specific TSC2 knockdown results in hypertrophy without contractile dysfunction.•mTORC1-induced cardiac hypertrophy is preceded by a decrease of glucose 6-phosphate isomerase levels and activity.•Activation of mTORC1 by voluntary exercise is associated with reduced TSC2 phosphorylation at Serine 1387.•In animals subjected to vuluntary exercise, changes in glucose 6-phosphate isomerase are present prior to hypertrophy.