Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion

Abstract

Background 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. Methods Cardiac glucose metabolism of male Tbc1d4-deficient (D4KO) and wild type (WT) mice was characterized using in vivo [18F]-FDG PET imaging after glucose injection and ex vivo basal/insulin-stimulated [3H]-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. Results 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. Conclusions 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.

Integrative single-cell characterization of a frugivorous and an insectivorous bat kidney and pancreas

“…8d ). We also observed insulin receptor substrate-1 ( IRS1 ), TBC1D4 , which regulates insulin-stimulated glucose uptake by controlling GLUT4 translocation 114 , and TOX , a transcriptional regulator in T1D 115 and associated with diabetic nephropathy 116 , to be upregulated in our fruit bat. The major gluconeogenesis regulator PCK1 and ketohexokinase gene KHK , which encodes the first enzyme to catabolize dietary fructose 117 , were downregulated.…”

Insulin signaling and its application

“…A truncated Arg363Ter mutation was identified in a family who suffered from postprandial hyperinsulinemia (64). A homozygous Arg684Ter variant of TBC1D4, which appeared with a great allele prevalence (17%) in the Greenlandic population, has shown a remarkable increase in the risk of the progress of type 2 diabetes (65). Deletion of TBC1D4 generating abolished glucose uptake negotiated by insulin is related to impaired glycemic control (66).…”

RICH1 is a novel key suppressor of isoproterenol‑ or angiotensin II‑induced cardiomyocyte hypertrophy

“…Notably, the inhibitory roles of RabGAPs and RasGAPs in cardiac hypertrophy have previously been reported ( 15 – 18 ). The ablation of the RabGAP TBC1 domain family member 1 results in significant cardiac hypertrophy in male rats and increased myocardial damage after ischemia/reperfusion ( 15 , 16 ). Similarly, depletion of Carabin, another RabGAP, can exacerbate cardiac hypertrophy and significantly reduce fractional shortening in mice ( 17 , 18 ).…”

“…GTPase-activating proteins (GaPs) can induce inactivation of small GTPases by inducing GTP hydrolysis (13,14). notably, the inhibitory roles of rabGaPs and rasGaPs in cardiac hypertrophy have previously been reported (15)(16)(17)(18). The ablation of the rabGaP TBC1 domain family member 1 results in significant cardiac hypertrophy in male rats and increased myocardial damage after ischemia/reperfusion (15,16).…”