TSC2 serine 1365 phosphorylation mediates murine HFpEF

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 TSC2^WT , TSC2^SE and TSC2^SA 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 TSC2^SA and a phospho-mimetic TSC2^SE KI mutation to induce mTORC1 hyperactivation (in TSC2^SA) and mTORC1 inhibition (in TSC2^SE). HFpEF WT mice show hyperphosphorylation of TSC^S1365. Phospho-mimetic TSC2^SE mice are protected against HF seen by reduced cardiac hypertrophy and improved diastolic function. TSC2^SE mice show significantly reduced HFD-induced obesity, thus improved glucose tolerance. Using metabolic cages these mice also demonstrate an improved respiratory exchange ratio (V_CO2/V_O2) 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 TSC2^SE, 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.