Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University Düsseldorf, Auf'm Hennekamp 65, 40225, Düsseldorf, Germany.
Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany.
Cardiovasc Diabetol. 2023 Jan 27;22(1):17. doi: 10.1186/s12933-023-01746-2.
Type 2 Diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and associated with poor outcome after myocardial infarction (MI). In T2DM, cardiac metabolic flexibility, i.e. the switch between carbohydrates and lipids as energy source, is disturbed. The RabGTPase-activating protein TBC1D4 represents a crucial regulator of insulin-stimulated glucose uptake in skeletal muscle by controlling glucose transporter GLUT4 translocation. A human loss-of-function mutation in TBC1D4 is associated with impaired glycemic control and elevated T2DM risk. The study's aim was to investigate TBC1D4 function in cardiac substrate metabolism and adaptation to MI.
Cardiac glucose metabolism of male Tbc1d4-deficient (D4KO) and wild type (WT) mice was characterized using in vivo [F]-FDG PET imaging after glucose injection and ex vivo basal/insulin-stimulated [H]-2-deoxyglucose uptake in left ventricular (LV) papillary muscle. Mice were subjected to cardiac ischemia/reperfusion (I/R). Heart structure and function were analyzed until 3 weeks post-MI using echocardiography, morphometric and ultrastructural analysis of heart sections, complemented by whole heart transcriptome and protein measurements.
Tbc1d4-knockout abolished insulin-stimulated glucose uptake in ex vivo LV papillary muscle and in vivo cardiac glucose uptake after glucose injection, accompanied by a marked reduction of GLUT4. Basal cardiac glucose uptake and GLUT1 abundance were not changed compared to WT controls. D4KO mice showed mild impairments in glycemia but normal cardiac function. However, after I/R D4KO mice showed progressively increased LV endsystolic volume and substantially increased infarction area compared to WT controls. Cardiac transcriptome analysis revealed upregulation of the unfolded protein response via ATF4/eIF2α in D4KO mice at baseline. Transmission electron microscopy revealed largely increased extracellular matrix (ECM) area, in line with decreased cardiac expression of matrix metalloproteinases of D4KO mice.
TBC1D4 is essential for insulin-stimulated cardiac glucose uptake and metabolic flexibility. Tbc1d4-deficiency results in elevated cardiac endoplasmic reticulum (ER)-stress response, increased deposition of ECM and aggravated cardiac damage following MI. Hence, impaired TBC1D4 signaling contributes to poor outcome after MI.
2 型糖尿病（T2DM）是心血管疾病的主要危险因素，与心肌梗死（MI）后的不良预后相关。在 T2DM 中，心脏代谢灵活性（即碳水化合物和脂质作为能量源的转换）受到干扰。RabGTPase 激活蛋白 TBC1D4 通过控制葡萄糖转运蛋白 GLUT4 易位，成为骨骼肌胰岛素刺激葡萄糖摄取的关键调节因子。人类 TBC1D4 功能丧失性突变与血糖控制受损和 T2DM 风险增加有关。本研究旨在研究 TBC1D4 在心脏底物代谢和适应 MI 中的功能。
通过静脉注射[F]-FDG 后行活体[F]-FDG PET 成像和左心室（LV）乳头肌基础/胰岛素刺激[H]-2-脱氧葡萄糖摄取的离体实验，对雄性 Tbc1d4 缺陷（D4KO）和野生型（WT）小鼠的心脏葡萄糖代谢进行了特征描述。对小鼠进行心脏缺血/再灌注（I/R）。通过超声心动图、心脏切片形态计量学和超微结构分析，以及全心脏转录组和蛋白质测量，在 MI 后 3 周内分析心脏结构和功能。
Tbc1d4 敲除消除了离体 LV 乳头肌和静脉注射后活体心脏葡萄糖摄取的胰岛素刺激，同时 GLUT4 显著减少。与 WT 对照组相比，基础心脏葡萄糖摄取和 GLUT1 丰度没有变化。与 WT 对照组相比，D4KO 小鼠的血糖轻度受损，但心脏功能正常。然而，在 I/R 后，与 WT 对照组相比，D4KO 小鼠的 LV 收缩末期容积逐渐增加，梗死面积明显增加。心脏转录组分析显示，D4KO 小鼠在基线时通过 ATF4/eIF2α 上调未折叠蛋白反应。透射电镜显示，D4KO 小鼠的细胞外基质（ECM）面积大大增加，与 D4KO 小鼠的基质金属蛋白酶心脏表达降低一致。
TBC1D4 对胰岛素刺激的心脏葡萄糖摄取和代谢灵活性至关重要。Tbc1d4 缺陷导致心脏内质网（ER）应激反应增加，ECM 沉积增加，MI 后心脏损伤加重。因此，TBC1D4 信号转导受损导致 MI 后预后不良。
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