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 RabGTP...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12933-023-01746-2 |
| _version_ | 1828051866948206592 |
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| author | C. Binsch D. M. Barbosa G. Hansen-Dille M. Hubert S. M. Hodge M. Kolasa K. Jeruschke J. Weiß C. Springer S. Gorressen J. W. Fischer M. Lienhard R. Herwig S. Börno B. Timmermann A. L. Cremer H. Backes A. Chadt H. Al-Hasani |
| author_facet | C. Binsch D. M. Barbosa G. Hansen-Dille M. Hubert S. M. Hodge M. Kolasa K. Jeruschke J. Weiß C. Springer S. Gorressen J. W. Fischer M. Lienhard R. Herwig S. Börno B. Timmermann A. L. Cremer H. Backes A. Chadt H. Al-Hasani |
| author_sort | C. Binsch |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T19:44:55Z |
| format | Article |
| id | doaj.art-1aa009e1fee843359a7e115e04fb7872 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-04-10T19:44:55Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-1aa009e1fee843359a7e115e04fb78722023-01-29T12:03:41ZengBMCCardiovascular Diabetology1475-28402023-01-0122111410.1186/s12933-023-01746-2Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusionC. Binsch0D. M. Barbosa1G. Hansen-Dille2M. Hubert3S. M. Hodge4M. Kolasa5K. Jeruschke6J. Weiß7C. Springer8S. Gorressen9J. W. Fischer10M. Lienhard11R. Herwig12S. Börno13B. Timmermann14A. L. Cremer15H. Backes16A. Chadt17H. Al-Hasani18Medical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfInstitute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-UniversityInstitute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-UniversityMax-Planck-Institute for Molecular GeneticsMax-Planck-Institute for Molecular GeneticsMax-Planck-Institute for Molecular GeneticsMax-Planck-Institute for Molecular GeneticsMax Planck Institute for Metabolism ResearchMax Planck Institute for Metabolism ResearchMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfMedical Faculty, Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz-Center for Diabetes Research at Heinrich Heine University DüsseldorfAbstract 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.https://doi.org/10.1186/s12933-023-01746-2Myocardial infarctionIschemia/reperfusionTBC1D4Metabolic flexibility |
| spellingShingle | C. Binsch D. M. Barbosa G. Hansen-Dille M. Hubert S. M. Hodge M. Kolasa K. Jeruschke J. Weiß C. Springer S. Gorressen J. W. Fischer M. Lienhard R. Herwig S. Börno B. Timmermann A. L. Cremer H. Backes A. Chadt H. Al-Hasani Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion Cardiovascular Diabetology Myocardial infarction Ischemia/reperfusion TBC1D4 Metabolic flexibility |
| title | Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion |
| title_full | Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion |
| title_fullStr | Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion |
| title_full_unstemmed | Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion |
| title_short | Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion |
| title_sort | deletion of tbc1d4 as160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia reperfusion |
| topic | Myocardial infarction Ischemia/reperfusion TBC1D4 Metabolic flexibility |
| url | https://doi.org/10.1186/s12933-023-01746-2 |
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