TSC2 serine 1365 phosphorylation mediates murine HFpEF

Shu Fu (Berlin)1, T. Wang (Berlin)1, M. Kirchner (Berlin)2, P. Mertins (Berlin)2, D. Kass (Baltimore)3, G. Schiattarella (Berlin)4, C. Oeing (Berlin)1

1Deutsches Herzzentrum der Charite (DHZC) Berlin, Deutschland; 2Max-Delbrück-Centrum für Molekulare Medizin Berlin, Deutschland; 3Johns Hopkins University Baltimore, USA; 4Charité - Universitätsmedizin Berlin CCR Center for Cardiovascular Research Berlin, Deutschland


The mechanistic target of rapamycin complex-1 (mTORC1) is a master regulator of protein synthesis, autophagy and metabolism. The tuberous sclerosis complex 2 (TSC2) is the main inhibitor of mTORC1. Its role in heart failure with preserved ejection fraction (HFpEF) though is unknown.

Using a global TSC2-knock-in (KI) model we can uniquely bidirectionally fine-tune mTORC1 after a pathological stimulus without losing its basal physiological function. To induce HFpEF, we feed TSC2WT , TSC2SE and TSC2SA mice with high fat diet (HFD) and 1g/l n[w]-nitro-l-arginine methyl ester (L-NAME) via drinking water for 15 weeks. We use KI mice expressing a phospho-silenced TSC2SA and a phospho-mimetic TSC2SE KI mutation to induce mTORC1 hyperactivation (in TSC2SA) and mTORC1 inhibition (in TSC2SE). HFpEF WT mice show hyperphosphorylation of TSCS1365. Phospho-mimetic TSC2SE mice are protected against HF seen by reduced cardiac hypertrophy and improved diastolic function. TSC2SE mice show significantly reduced HFD-induced obesity, thus improved glucose tolerance. Using metabolic cages these mice also demonstrate an improved respiratory exchange ratio (VCO2/VO2) and energy expenditure. Adipose tissue reveals an altered metabolic gene expression. This protection cannot be observed in HFD alone and leptin-deficient (dbdb) mice expressing TSC2SE, thus extra-cardiac effects of L-NAME likely mediate a mTORC1-dependent mechanism to induce HFpEF. Proteomics from heart tissue reveal a distinct signature from systemically metabolic active proteins that might contribute to the failing heart.   

Conclusion: mTORC1 inhibiting TSC2SE mutant mice are protected against HFpEF illustrating improved cardiac function, improved metabolic rates, reduced fat mass and improved fat metabolism and glucose tolerance. mTORC1 inhibiting might represent a therapeutic approach to improve metabolic syndrome and cardiac function in HFpEF.

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