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

TSC2 S1365 phosphorylation status mediates diabetic cardiomyopathy
S. Sohns1, S. FU1, B. Pieske2, C. Oeing2
1Charité - Universitätsmedizin Berlin, Berlin; 2CC11: Med. Klinik m.S. Kardiologie, Charité - Universitätsmedizin Berlin, Berlin;

Rationale: The protein kinase mechanistic target of rapamycin complex-1 (mTORC1) is a key regulator for cell metabolism, protein homeostasis and autophagy. Latest studies show that phosphorylation status of serine 1365 on tuberous sclerosis complex (TSC2) regulates mTORC1 bi-directionally. The phosphorylated S1365 on TSC2 decreases, and  dephosphorylated S1365 increases mTOR activity in heart failure with reduced ejection fraction. The role of S1365 in diabetic cardiomyopathy remains unknown.

Objective: We study the importance of TSC2-mTOR signaling via TSC2-S1365 in type 1 diabetes mellitus (T1DM) and its influence on heart function and cell metabolism.

Methods and results: We use a T1DM mouse model with either TSC2-S1365A (TSC2SA; phospho-null) or TSC2-S1365E (TSC2SE; phosphomimetic) knock-in mutations and littermate wildtype controls. T1DM was induced by intraperitoneal streptozotocin (STZ) injections (55mg/kg body weight for 5 consecutive days). Glucose monitoring, intraperitoneal glucose tolerance tests, body composition imaging, non-invasive blood pressure and metabolic in vivo measurements, as well as echocardiography was performed. T1DM was successfully induced in all groups characterized by significant hyperglycemia (fasting glucose in sham TSC2WT vs. STZ-treated TSC2WT vs TSC2SE vs TSCSA: 6.35±1.047mmol/l vs. 25.87±5.162mmol/l vs. 27,73±2.214mmol/l vs. 27.02±1.034mmol/l, Sham vs. all STZ-treated groups: p<0.001) as well as weight gain/loss with no significant differences between different genotypes (STZ-treated TSC2WT vs TSC2SE vs TSC2SA: 2.65±2.549g vs. -0,2±0.981g vs. -0.06±1g vs. -1.975 ±1.565g, p>0.05). In contrast, TSC2SA mutant mice characterized by mTORC1 hyperactivation show reduced oxygen consumption (sham TSC2WT vs. STZ-treated TSC2WT vs TSC2SE vs TSC2SA: 113.4±7.714ml/h vs. 106.3±17.48ml/h vs. 105.4±2.959ml/h vs. 99.41±6.031ml/h, TSC2SE vs. TSC2SA p=0.15) and CO2 production (sham TSC2WT vs. STZ treated TSC2WT vs. TSC2SE vs. TSC2SA: 97.89±9.182 ml/h vs. 83.72±7.602ml/h vs. 83.87±2.093ml/h vs. 78.24±5.376ml/h, TSC2SE vs. TSC2SA p=0.12) and show worsened diabetic cardiomyopathy marked by mildly reduced systolic (ejection fraction) (sham TSC2WT vs. STZ-treated TSC2WT vs TSC2SE vs TSC2SA: 97.89±9.182ml/h vs. 63.98±5.534% vs. 64.96±3.501% vs. 52.0±2.93%, TSC2SE vs. TSC2SA p=0.002).

Conclusions: TSC2-S1365 phosphorylation status impacts the cardiac function and the metabolic system in T1DM. Dephosphorylation mimicked by the SA mutant increases mTOR activity and leads to worsened diastolic dysfunction and metabolic performance.

 

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