HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-02-03 DOI:10.1016/j.molmet.2025.102107

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

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引用次数: 0

Abstract

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".

Abstract Image

查看原文本刊更多论文

HINT1抑制通过增强线粒体生物发生预防年龄相关性心功能障碍。

心功能随着年龄的增长而下降，损害运动耐量，对健康衰老产生负面影响。在这里，我们观察到老年小鼠心脏中线粒体生物发生失活和线粒体质量减少。我们还发现，BAF染色质重塑复合体的活性受到HINT1的抑制，其在心脏中的表达随着年龄的增长而增加，导致Tfam转录减少，从而促进线粒体的生物发生。有趣的是，热量限制（CR）不仅抑制了与年龄相关的心功能和线粒体生物发生的下降，还阻止了心脏HINT1蛋白水平的增加，并维持了Tfam转录。此外，抑制Hint1 mRNA翻译的lncRNA Caren的表达随着年龄的增长而下降，而CR抑制了这一作用。最后，由于Caren过表达而导致的HINT1表达减少，可以对抗线粒体生物发生的年龄相关下降，改善年龄相关的心功能障碍、运动不耐受、运动引起的心脏损伤和随后的小鼠死亡。这些数据表明，总的来说，caren - hint1 -线粒体生物发生轴代表了cr诱导的心脏衰老抵抗的重要机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.