Effect of Chronic Treatment with Uridine on Cardiac Mitochondrial Dysfunction in the C57BL/6 Mouse Model of High-Fat Diet–Streptozotocin-Induced Diabetes
Long-term hyperglycemia in diabetes mellitus is associated with complex damage to cardiomyocytes and the development of mitochondrial dysfunction in the myocardium. Uridine, a pyrimidine nucleoside, plays an important role in cellular metabolism and is used to improve cardiac function. Herein, the a...
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2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/18/10633 |
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| author | Natalia V. Belosludtseva Vlada S. Starinets Irina B. Mikheeva Maxim N. Belosludtsev Mikhail V. Dubinin Galina D. Mironova Konstantin N. Belosludtsev |
| author_facet | Natalia V. Belosludtseva Vlada S. Starinets Irina B. Mikheeva Maxim N. Belosludtsev Mikhail V. Dubinin Galina D. Mironova Konstantin N. Belosludtsev |
| author_sort | Natalia V. Belosludtseva |
| collection | DOAJ |
| description | Long-term hyperglycemia in diabetes mellitus is associated with complex damage to cardiomyocytes and the development of mitochondrial dysfunction in the myocardium. Uridine, a pyrimidine nucleoside, plays an important role in cellular metabolism and is used to improve cardiac function. Herein, the antidiabetic potential of uridine (30 mg/kg/day for 21 days, i.p.) and its effect on mitochondrial homeostasis in the heart tissue were examined in a high-fat diet–streptozotocin-induced model of diabetes in C57BL/6 mice. We found that chronic administration of uridine to diabetic mice normalized plasma glucose and triglyceride levels and the heart weight/body weight ratio and increased the rate of glucose utilization during the intraperitoneal glucose tolerance test. Analysis of TEM revealed that uridine prevented diabetes-induced ultrastructural abnormalities in mitochondria and sarcomeres in ventricular cardiomyocytes. In diabetic heart tissue, the mRNA level of <i>Ppargc1a</i> decreased and <i>Drp1</i> and <i>Parkin</i> gene expression increased, suggesting the disturbances of mitochondrial biogenesis, fission, and mitophagy, respectively. Uridine treatment of diabetic mice restored the mRNA level of <i>Ppargc1a</i> and enhanced <i>Pink1</i> gene expression, which may indicate an increase in the intensity of mitochondrial biogenesis and mitophagy, and as a consequence, mitochondrial turnover. Uridine also reduced oxidative phosphorylation dysfunction and suppressed lipid peroxidation, but it had no significant effect on the impaired calcium retention capacity and potassium transport in the heart mitochondria of diabetic mice. Altogether, these findings suggest that, along with its hypoglycemic effect, uridine has a protective action against diabetes-mediated functional and structural damage to cardiac mitochondria and disruption of mitochondrial quality-control systems in the diabetic heart. |
| first_indexed | 2024-03-09T23:45:15Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:45:15Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-dfea4e271e1b4365b993a1e9cd3e7f112023-11-23T16:45:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123181063310.3390/ijms231810633Effect of Chronic Treatment with Uridine on Cardiac Mitochondrial Dysfunction in the C57BL/6 Mouse Model of High-Fat Diet–Streptozotocin-Induced DiabetesNatalia V. Belosludtseva0Vlada S. Starinets1Irina B. Mikheeva2Maxim N. Belosludtsev3Mikhail V. Dubinin4Galina D. Mironova5Konstantin N. Belosludtsev6Laboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino 142290, RussiaLaboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino 142290, RussiaLaboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino 142290, RussiaDepartment of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, Yoshkar-Ola 424001, RussiaDepartment of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, Yoshkar-Ola 424001, RussiaLaboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino 142290, RussiaLaboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, Pushchino 142290, RussiaLong-term hyperglycemia in diabetes mellitus is associated with complex damage to cardiomyocytes and the development of mitochondrial dysfunction in the myocardium. Uridine, a pyrimidine nucleoside, plays an important role in cellular metabolism and is used to improve cardiac function. Herein, the antidiabetic potential of uridine (30 mg/kg/day for 21 days, i.p.) and its effect on mitochondrial homeostasis in the heart tissue were examined in a high-fat diet–streptozotocin-induced model of diabetes in C57BL/6 mice. We found that chronic administration of uridine to diabetic mice normalized plasma glucose and triglyceride levels and the heart weight/body weight ratio and increased the rate of glucose utilization during the intraperitoneal glucose tolerance test. Analysis of TEM revealed that uridine prevented diabetes-induced ultrastructural abnormalities in mitochondria and sarcomeres in ventricular cardiomyocytes. In diabetic heart tissue, the mRNA level of <i>Ppargc1a</i> decreased and <i>Drp1</i> and <i>Parkin</i> gene expression increased, suggesting the disturbances of mitochondrial biogenesis, fission, and mitophagy, respectively. Uridine treatment of diabetic mice restored the mRNA level of <i>Ppargc1a</i> and enhanced <i>Pink1</i> gene expression, which may indicate an increase in the intensity of mitochondrial biogenesis and mitophagy, and as a consequence, mitochondrial turnover. Uridine also reduced oxidative phosphorylation dysfunction and suppressed lipid peroxidation, but it had no significant effect on the impaired calcium retention capacity and potassium transport in the heart mitochondria of diabetic mice. Altogether, these findings suggest that, along with its hypoglycemic effect, uridine has a protective action against diabetes-mediated functional and structural damage to cardiac mitochondria and disruption of mitochondrial quality-control systems in the diabetic heart.https://www.mdpi.com/1422-0067/23/18/10633mitochondriadiabetes mellitusuridinemitochondrial dysfunctionlipid peroxidationmitochondrial biogenesis |
| spellingShingle | Natalia V. Belosludtseva Vlada S. Starinets Irina B. Mikheeva Maxim N. Belosludtsev Mikhail V. Dubinin Galina D. Mironova Konstantin N. Belosludtsev Effect of Chronic Treatment with Uridine on Cardiac Mitochondrial Dysfunction in the C57BL/6 Mouse Model of High-Fat Diet–Streptozotocin-Induced Diabetes International Journal of Molecular Sciences mitochondria diabetes mellitus uridine mitochondrial dysfunction lipid peroxidation mitochondrial biogenesis |
| title | Effect of Chronic Treatment with Uridine on Cardiac Mitochondrial Dysfunction in the C57BL/6 Mouse Model of High-Fat Diet–Streptozotocin-Induced Diabetes |
| title_full | Effect of Chronic Treatment with Uridine on Cardiac Mitochondrial Dysfunction in the C57BL/6 Mouse Model of High-Fat Diet–Streptozotocin-Induced Diabetes |
| title_fullStr | Effect of Chronic Treatment with Uridine on Cardiac Mitochondrial Dysfunction in the C57BL/6 Mouse Model of High-Fat Diet–Streptozotocin-Induced Diabetes |
| title_full_unstemmed | Effect of Chronic Treatment with Uridine on Cardiac Mitochondrial Dysfunction in the C57BL/6 Mouse Model of High-Fat Diet–Streptozotocin-Induced Diabetes |
| title_short | Effect of Chronic Treatment with Uridine on Cardiac Mitochondrial Dysfunction in the C57BL/6 Mouse Model of High-Fat Diet–Streptozotocin-Induced Diabetes |
| title_sort | effect of chronic treatment with uridine on cardiac mitochondrial dysfunction in the c57bl 6 mouse model of high fat diet streptozotocin induced diabetes |
| topic | mitochondria diabetes mellitus uridine mitochondrial dysfunction lipid peroxidation mitochondrial biogenesis |
| url | https://www.mdpi.com/1422-0067/23/18/10633 |
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