Abstract 14424: mTORcise: Replicating Exercise Induced Remodeling of the Heart by targeted deletion of Tuberin.
Introduction: When stressed, the heart remodels metabolically and structurally. Metabolically, the heart increases its reliance on carbohydrates for energy provision, while structurally, it hypertrophies. Whether both processes occur independently, or if they are interrelated is not known. In the heart, the activation of the mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway is closely tied to glucose metabolism and cellular growth, and is therefore a potential link between these two types of remodeling.
Objective: We examined whether long-term, sustained mTORC1 activation results in metabolic and structural remodeling in the heart, with a focus on the time course of these events.
Methods: We developed a mouse model of inducible, cardiac-specific deficiency of tuberin (TSC2), a key inhibitor of mTORC1. TSC2 gene recombination was induced between 5-7 weeks of age, and echocardiograms were performed at 4, 10 and 20 weeks after induction. Genomic DNA, total RNA and proteins were extracted from freeze-clamped hearts for PCR, real-time PCR and immunoblotting respectively. Glucose 6-phosphate (G6P) levels were measured by spectrophotometric enzymatic analysis. Histologic analysis using H/E and Masson’s Trichrome stains were used to determine cardiomyocyte area and interstitial fibrosis.
Results: Immunoblotting of protein markers confirmed TSC2 knockout (KO) and activation of mTORC1 downstream targets as early as two weeks after induction. G6P was increased 4 weeks after induction, before any structural changes were detected. Serial echocardiograms revealed concentric remodeling 10 weeks after induction, which persisted at 20 weeks. Furthermore, the systolic function in the conditional KO animals was greater than the controls 20 weeks after induction. Cardiomyocytes hypertrophied at 20 weeks, without any evidence of increase in fibrosis.
Conclusions: Inducible, sustained mTORC1 activation by TSC2 KO in the heart triggers physiologic remodeling, characterized by cardiomyocyte hypertrophy, concentric remodeling and improved systolic function. This phenotype is similar to the one induced by strength-training. Lastly, we show that metabolic remodeling precedes this type of structural remodeling.
Author Disclosures: G. Davogustto: None. R. Salazar: None. H. Vasquez: None. P. Guthrie: None. H. Taegtmeyer: None.
- © 2016 by American Heart Association, Inc.