Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

TSC2-mTORC1 signaling in murine Heart Failure with Preserved Ejection Fraction
S. FU1, S. Sohns2, B. Pieske1, C. Oeing3
1Charité - Universitätsmedizin Berlin, Berlin; 2Kardiologie, Leitung / Mittelallee 11 / 2. Stock, Charité - Universitätsmedizin Berlin, Berlin; 3CC11: Med. Klinik m.S. Kardiologie, Charité - Universitätsmedizin Berlin, Berlin;

Rationale: The role of mechanistic target of rapamycin complex-1 (mTORC1) in heart failure with preserved ejection fraction (HFpEF) is unknown. The tuberous sclerosis complex 2 (TSC2) is the main inhibitor of mTORC1 which mediates protein synthesis, autophagy and metabolism. We use a unique TSC2-knock-in model to better understand mTOR signaling in HFpEF. 

Objective: We investigate the role of mTORC1 deactivation and hyperactivation in murine HFpEF.


Methods and results:
 We use knock-in mice expressing a phospho-silenced TSC2 (S1365A, TSC2SA) and a phospho-mimetic TSC2 (S1365E, TSC2SE) mutation to induce mTORC1 hyperactivation (in TSC2SA) and mTORC1 inhibition (in TSC2SE). To induce HFpEF, we feed TSC2WT, TSC2SE and TSC2SA mice with high fat diet (HFD) and N[w]-nitro-l-arginine methyl ester (L-NAME) via the drinking water for a total of 15 weeks. Metabolic cages are used to determine of CO2 elimination, and rate of O2consumption. We use lung weight (wet-to-dry ratio) to assess lung congestion. We measured glucose tolerance via intraperitoneal glucose injection and use magnetic resonance imaging for detection of body composition. We performed echocardiography to evaluate diastolic and systolic function. As expected, HFD resulted in significant weight gain and glucose intolerance. While there is no difference in weight gain between genotypes, TSC2SE mice have improved glucose tolerance (AUC of TSC2SE vs TSC2SA: 27972.4±381.1 vs 33572±973.9, p=0.2397, n=5 per group). In TSC2SA mutant mice, we observe reduced O2 consumption (VO2) and CO2 elimination (VCO2) in comparison to TSC2WT mice. In contrast, in TSC2SE we see increased VO2 and VCO2 (Light VO2, SE vs SA: 5846.3±59.9 vs 4962.2±42.4, p=0.0055. Dark: VO2, 6827.6±88.9 vs 5513.9±32.7, p<0.0001. Light: VCO2, SE vs SA: 3955.4±34.1 vs 3402.3±35.5, p=0.0197. Dark: VCO2, 4532.8±56.5 vs 3787.5±32.4, p=0.0012; n=5 per group.). HFpEF mice exhibited an increase in lung weight indicating lung congestion which was ameliorated in TSC2SE suggesting improved cardiac performance in TSC2SE mice and worsened heart failure in TSC2SA mice (TSC2SE vs TSC2SA: 9.6±0.6 vs 10.8±0.5, p=0.7232, n=5 per group). Ultimately, TSC2SA show mildly worsened systolic and diastolic function compared with TSC2SE (ejection fraction SE vs. SA: 74.3±0.6 vs. 68.2 ±0.7, p= 0.0059, n=5 per group).

Conclusions: TSC2SE mutant mice characterized by inhibited mTOR signaling are mildly protected in a murine model of HFpEF while TSC2SA mutant mice, which exhibit mTOR hyperactivation, show signs of worsened heart failure. 


https://dgk.org/kongress_programme/jt2022/aP441.html