Abstract 102: Cardiac-specific Overactivation of the Mechanistic Target of Rapamycin Complex 1 Induces Metabolic, Structural and Functional Remodeling

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The heart remodels metabolically and structurally before it fails. Metabolically, the heart increases its reliance on carbohydrates for energy provision. Structurally, the heart hypertrophies to sustain increased hemodynamic stress. There is evidence suggesting that the activation of the mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway is closely tied to glucose uptake by the heart to drive the metabolic and structural remodeling. We have previously shown that with insulin stimulation or increases in workload, the glycolytic intermediate glucose 6-phosphate (G6P) is required to activate mTORC1. Sustained mTORC1 activation leads, in turn, to ER stress and contractile dysfunction. Studies by others in the kidney have shown that mTORC1 activation upregulates glucose transporter 1 (Glut1) expression and glucose uptake. We therefore test the hypothesis that chronic mTORC1 overactivation results in G6P accumulation, and precedes structural and functional remodeling in the heart. We developed mice with inducible, cardiac-specific deficiency of the protein tuberin (TSC2), a member of the tuberous sclerosis complex, the principal inhibitor of mTORC1. Intracellular G6P concentrations were measured enzymatically. Immunoblotting was performed on protein markers to confirm activation of mTORC1 downstream targets and of the unfolded protein response. Histologic analysis were performed to assess structural changes. Serial echocardiograms were performed to evaluate cardiac function. The results indicate that chronic mTORC1 activation through inducible, cardiac-specific deletion of TSC2 is accompanied by G6P accumulation and metabolic remodeling. Metabolic remodeling precedes structural and functional remodeling. We suggest that in the heart, sustained mTORC1 activation is a key driver of metabolic and structural remodeling.