The antibiotic doxycycline impairs cardiac mitochondrial and contractile function
| Autor: | Diederik W. D. Kuster, Michel van Weeghel, Vida Alizadeh Tazehkandi, Luciënne Baks-Te Bulte, Gustav J. Strijkers, Bram F. Coolen, Ntsiki M. Held, Bianca J. J. M. Brundel, Riekelt H. Houtkooper, Mariah R R Daal, Marit Wiersma, Rob C. I. Wüst |
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| Přispěvatelé: | Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, AMS - Amsterdam Movement Sciences, Graduate School, ACS - Diabetes & metabolism, ANS - Brain Imaging, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Heart failure & arrhythmias, AMS - Musculoskeletal Health, AMS - Sports, Physiology, AMS - Ageing & Vitality, Clinical chemistry |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cytosol/metabolism Electron Transport Complex I/metabolism Male Aging Mitochondrial translation 030204 cardiovascular system & hematology Mitochondrion Inbred C57BL Mitochondria Heart Oxidative Phosphorylation lcsh:Chemistry Mitochondria Heart/drug effects Mice 0302 clinical medicine Cytosol Diastole Glucose/metabolism Glycolysis Myocytes Cardiac Experimental/pathology lcsh:QH301-705.5 Spectroscopy Oxidative Phosphorylation/drug effects Doxycycline Ejection fraction Chemistry Electron Transport Complex II Nuclear Proteins General Medicine Computer Science Applications Anti-Bacterial Agents Mitochondria Drosophila melanogaster Drosophila melanogaster/drug effects Calcium Signaling/drug effects Myocardial Contraction/drug effects Electron Transport Complex II/metabolism medicine.drug medicine.medical_specialty Myocytes Cardiac/drug effects Calcium/metabolism Mitochondrial Proteins/metabolism Cell Respiration Oxidative phosphorylation Catalysis Article Diabetes Mellitus Experimental Anti-Bacterial Agents/pharmacology Inorganic Chemistry Contractility Mitochondrial Proteins Doxycycline/pharmacology 03 medical and health sciences Glycolysis/drug effects SDG 3 - Good Health and Well-being Internal medicine medicine Cell Respiration/drug effects Diabetes Mellitus Animals Diabetes Mellitus Experimental/pathology Calcium Signaling Calcium handling Physical and Theoretical Chemistry Molecular Biology Diastole/drug effects Nuclear Proteins/metabolism Myocytes Electron Transport Complex I Organic Chemistry Myocardial Contraction Heart/drug effects Rats Mice Inbred C57BL Aging/metabolism 030104 developmental biology Endocrinology Glucose Cardiac/drug effects lcsh:Biology (General) lcsh:QD1-999 Cardiac contractility Calcium Mitochondrial function |
| Zdroj: | Wüst, R C I, Coolen, B F, Held, N M, Daal, M R R, Tazehkandi, V A, Baks-Te Bulte, L, Wiersma, M, Kuster, D W D, Brundel, B J J M, van Weeghel, M, Strijkers, G J & Houtkooper, R H 2021, ' The antibiotic doxycycline impairs cardiac mitochondrial and contractile function ', International Journal of Molecular Sciences, vol. 22, no. 8, 4100 . https://doi.org/10.3390/ijms22084100 International journal of molecular sciences, 22(8):4100. Multidisciplinary Digital Publishing Institute (MDPI) International Journal of Molecular Sciences, 22(8):4100, 1-19. Multidisciplinary Digital Publishing Institute (MDPI) International Journal of Molecular Sciences Volume 22 Issue 8 Wüst, R C I, Coolen, B F, Held, N M, Daal, M R R, Tazehkandi, V A, Baks-Te Bulte, L, Wiersma, M, Kuster, D W D, Brundel, B J J M, van Weeghel, M, Strijkers, G J & Houtkooper, R H 2021, ' The antibiotic doxycycline impairs cardiac mitochondrial and contractile function ', International Journal of Molecular Sciences, vol. 22, no. 8, 4100, pp. 1-19 . https://doi.org/10.3390/ijms22084100 International Journal of Molecular Sciences, 22(8):4100. Multidisciplinary Digital Publishing Institute (MDPI) International Journal of Molecular Sciences, Vol 22, Iss 4100, p 4100 (2021) |
| ISSN: | 1422-0067 1661-6596 |
| DOI: | 10.3390/ijms22084100 |
| Popis: | Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosophila and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and Drosophila melanogaster hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction. |
| Databáze: | OpenAIRE |
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