HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis
Objective: Cardiac function declines with age, impairing exercise tolerance and negatively impacting healthy aging. However, mechanisms driving age-related declines in cardiac function are not fully understood. Methods: We examined mechanisms underlying age-related cardiac dysfunction using 3- and 2...
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| Language: | English |
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Elsevier
2025-03-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000146 |
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| author | Michio Sato Tsuyoshi Kadomatsu Jun Morinaga Yuya Kinoshita Daisuke Torigoe Haruki Horiguchi Sumio Ohtsuki Shuji Yamamura Ryoko Kusaba Takanori Yamaguchi Goro Yoshioka Kimi Araki Tomohiko Wakayama Keishi Miyata Koichi Node Yuichi Oike |
| author_facet | Michio Sato Tsuyoshi Kadomatsu Jun Morinaga Yuya Kinoshita Daisuke Torigoe Haruki Horiguchi Sumio Ohtsuki Shuji Yamamura Ryoko Kusaba Takanori Yamaguchi Goro Yoshioka Kimi Araki Tomohiko Wakayama Keishi Miyata Koichi Node Yuichi Oike |
| author_sort | Michio Sato |
| collection | DOAJ |
| description | Objective: Cardiac function declines with age, impairing exercise tolerance and negatively impacting healthy aging. However, mechanisms driving age-related declines in cardiac function are not fully understood. Methods: We examined mechanisms underlying age-related cardiac dysfunction using 3- and 24-month-old wild-type mice fed ad libitum or 24-month-old wild-type mice subjected to 70% calorie restriction (CR) starting at 2-month-old. In addition, cardiac aging phenotypes and mitochondrial biogenesis were also analyzed in 25-month-old cardiac-specific Hint1 knockout mice, 24-month-old CAG-Caren Tg mice, and 24-month-old wild-type mice injected with AAV6-Caren. Results: We observed inactivation of mitochondrial biogenesis in hearts of aged mice. We also showed that activity of the BAF chromatin remodeling complex is repressed by HINT1, whose expression in heart increases with age, leading to decreased transcription of Tfam, which promotes mitochondrial biogenesis. Interestingly, CR not only suppressed age-related declines in cardiac function and mitochondrial biogenesis but blocked concomitant increases in cardiac HINT1 protein levels and maintained Tfam transcription. Furthermore, expression of the lncRNA Caren, which inhibits Hint1 mRNA translation, decreased with age in heart, and CR suppressed this effect. Finally, decreased HINT1 expression due to Caren overexpression antagonized age-related declines in mitochondrial biogenesis, ameliorating age-related cardiac dysfunction, exercise intolerance, and exercise-induced cardiac damage and subsequent death of mice. Conclusion: Our findings suggest that mitochondrial biogenesis in cardiomyocytes decreases with age and could underlie cardiac dysfunction, and that the Caren-HINT1-mitochondrial biogenesis axis may constitute a mechanism linking CR to resistance to cardiac aging. We also show that ameliorating declines in mitochondrial biogenesis in cardiomyocytes could counteract age-related declines in cardiac function, and that this strategy may improve exercise tolerance and extend so-called ''healthy life span''. |
| format | Article |
| id | doaj-art-f563620736254457af06cdebb7c52e58 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-f563620736254457af06cdebb7c52e582025-02-09T05:00:17ZengElsevierMolecular Metabolism2212-87782025-03-0193102107HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesisMichio Sato0Tsuyoshi Kadomatsu1Jun Morinaga2Yuya Kinoshita3Daisuke Torigoe4Haruki Horiguchi5Sumio Ohtsuki6Shuji Yamamura7Ryoko Kusaba8Takanori Yamaguchi9Goro Yoshioka10Kimi Araki11Tomohiko Wakayama12Keishi Miyata13Koichi Node14Yuichi Oike15Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan; Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Division of Kumamoto Mouse Clinic (KMC), Institute of Resource Developmental and Analysis (IRDA), Kumamoto University, Kumamoto, Japan; Department of Cardiovascular Medicine, School of Medicine, Saga University, Saga, JapanDepartment of Molecular Genetics, Kumamoto University, Kumamoto, Japan; Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanDepartment of Molecular Genetics, Kumamoto University, Kumamoto, JapanDepartment of Molecular Genetics, Kumamoto University, Kumamoto, JapanDivision of Experimental Genetics, IRDA, Kumamoto University, Kumamoto, JapanDepartment of Molecular Genetics, Kumamoto University, Kumamoto, Japan; Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanDepartment of Pharmaceutical Microbiology, Graduate School of Pharmacological Sciences, Kumamoto University, Kumamoto, JapanDepartment of Molecular Genetics, Kumamoto University, Kumamoto, JapanDepartment of Molecular Genetics, Kumamoto University, Kumamoto, JapanDepartment of Cardiovascular Medicine, School of Medicine, Saga University, Saga, JapanDepartment of Cardiovascular Medicine, School of Medicine, Saga University, Saga, JapanCenter for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Division of Developmental Genetics, IRDA, Kumamoto University, Kumamoto, JapanDepartment of Histology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanDepartment of Molecular Genetics, Kumamoto University, Kumamoto, JapanDepartment of Cardiovascular Medicine, School of Medicine, Saga University, Saga, JapanDepartment of Molecular Genetics, Kumamoto University, Kumamoto, Japan; Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Corresponding author. Department of Molecular Genetics, Kumamoto University, Kumamoto, Japan.Objective: Cardiac function declines with age, impairing exercise tolerance and negatively impacting healthy aging. However, mechanisms driving age-related declines in cardiac function are not fully understood. Methods: We examined mechanisms underlying age-related cardiac dysfunction using 3- and 24-month-old wild-type mice fed ad libitum or 24-month-old wild-type mice subjected to 70% calorie restriction (CR) starting at 2-month-old. In addition, cardiac aging phenotypes and mitochondrial biogenesis were also analyzed in 25-month-old cardiac-specific Hint1 knockout mice, 24-month-old CAG-Caren Tg mice, and 24-month-old wild-type mice injected with AAV6-Caren. Results: We observed inactivation of mitochondrial biogenesis in hearts of aged mice. We also showed that activity of the BAF chromatin remodeling complex is repressed by HINT1, whose expression in heart increases with age, leading to decreased transcription of Tfam, which promotes mitochondrial biogenesis. Interestingly, CR not only suppressed age-related declines in cardiac function and mitochondrial biogenesis but blocked concomitant increases in cardiac HINT1 protein levels and maintained Tfam transcription. Furthermore, expression of the lncRNA Caren, which inhibits Hint1 mRNA translation, decreased with age in heart, and CR suppressed this effect. Finally, decreased HINT1 expression due to Caren overexpression antagonized age-related declines in mitochondrial biogenesis, ameliorating age-related cardiac dysfunction, exercise intolerance, and exercise-induced cardiac damage and subsequent death of mice. Conclusion: Our findings suggest that mitochondrial biogenesis in cardiomyocytes decreases with age and could underlie cardiac dysfunction, and that the Caren-HINT1-mitochondrial biogenesis axis may constitute a mechanism linking CR to resistance to cardiac aging. We also show that ameliorating declines in mitochondrial biogenesis in cardiomyocytes could counteract age-related declines in cardiac function, and that this strategy may improve exercise tolerance and extend so-called ''healthy life span''.http://www.sciencedirect.com/science/article/pii/S2212877825000146Cardiac agingHeart failureMitochondrial biogenesisCalorie restriction |
| spellingShingle | Michio Sato Tsuyoshi Kadomatsu Jun Morinaga Yuya Kinoshita Daisuke Torigoe Haruki Horiguchi Sumio Ohtsuki Shuji Yamamura Ryoko Kusaba Takanori Yamaguchi Goro Yoshioka Kimi Araki Tomohiko Wakayama Keishi Miyata Koichi Node Yuichi Oike HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis Molecular Metabolism Cardiac aging Heart failure Mitochondrial biogenesis Calorie restriction |
| title | HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis |
| title_full | HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis |
| title_fullStr | HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis |
| title_full_unstemmed | HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis |
| title_short | HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis |
| title_sort | hint1 suppression protects against age related cardiac dysfunction by enhancing mitochondrial biogenesis |
| topic | Cardiac aging Heart failure Mitochondrial biogenesis Calorie restriction |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000146 |
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