Restoration of Cardiomyogenesis in Aged Mouse Hearts by Voluntary Exercise.
Restoration of Cardiomyogenesis in Aged Mouse Hearts by Voluntary Exercise.
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随意运动对老年小鼠心脏心肌发生的恢复作用。
DOI：
10.1161/circulationaha.121.057276
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发表时间：
2022-08-02
期刊：
影响因子：
37.8
通讯作者：
Lee, Richard T.
中科院分区：
文献类型：
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作者：
Lerchenmueller, Carolin;Vujic, Ana;Mittag, Sonja;Wang, Annie;Rabolli, Charles P.;Hess, Chiara;Betge, Fynn;Rangrez, Ashraf Y.;Chaklader, Malay;Guillermier, Christelle;Gyngard, Frank;Roh, Jason D.;Li, Haobo;Steinhauser, Matthew L.;Frey, Norbert;Rothermel, Beverly;Dieterich, Christoph;Rosenzweig, Anthony;Lee, Richard T.
人类心脏产生新心肌细胞的能力有限，这种能力随着年龄的增长而下降。由于心肌细胞的损失可能导致心力衰竭，因此探索内源性心脏再生的刺激，以有利地改变衰老心脏中心肌细胞损失和新心肌细胞生成之间的平衡是至关重要的。我们之前已经证明，运动可以激活年轻成年小鼠心脏的心肌生成。然而，运动是否也能诱导老年心脏的心肌生成，目前尚不清楚。在这里，我们的目的是研究运动对老年心脏新心肌细胞生成的影响。年龄较大（20个月）的小鼠接受为期8周的自愿跑步方案，而年龄匹配的久坐动物作为对照。基于15n -胸腺嘧啶掺入和多同位素成像质谱法（MIMS）评估老年心脏的心肌发生。我们分析了来自5只老年久坐小鼠的1793个心肌细胞，并将其与来自5只老年运动小鼠的2002个心肌细胞进行了比较，随后进行了先进的组织学和成像，以解释细胞的倍性和成核状态。进行RNA测序和随后的生物信息学分析，以研究运动引起的转录变化，特别是老年心脏与年轻心脏的比较。通过检测单核/二倍体15n -胸腺嘧啶标记的心肌细胞，观察到与久坐的老年心脏相比，运动时心肌发生的频率明显更高。在久坐衰老小鼠中未检测到单核/二倍体15n -胸腺嘧啶标记心肌细胞。老年运动小鼠单核/二倍体15n -胸腺嘧啶标记心肌细胞的年增长率为每年2.3%。相比之下，我们之前报道的年轻运动小鼠的年增长率为7.5%，年轻久坐小鼠的年增长率为1.63%。对年轻和老年运动小鼠心脏及其久坐对照组的转录谱分析显示，运动诱导了与昼夜节律相关的通路，与年龄无关。然而，一种已知的振荡转录本，在老年运动心脏中只上调，是RCAN1.4，其调节和功能作用被进一步探索。我们的数据表明，自愿跑步可以部分恢复老年小鼠的心肌形成，并表明与昼夜节律相关的途径可能在生理刺激的心肌形成中发挥作用。
The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in the aged heart. We have previously shown that cardiomyogenesis can be activated by exercise in the young adult mouse heart. Whether exercise also induces cardiomyogenesis in aged hearts, however, is yet unknown. Here, we aim to investigate the effect of exercise on generation of new cardiomyocytes in the aged heart. Aged (20-months) mice were subjected to an eight-week voluntary running protocol, and age-matched sedentary animals served as controls. Cardiomyogenesis in aged hearts was assessed based on 15N-thymidine incorporation and multi-isotope imaging mass spectrometry (MIMS). We analyzed 1793 cardiomyocytes from five aged sedentary mice and compared these to 2002 cardiomyocytes from five aged, exercised mice followed by advanced histology and imaging to account for ploidy and nucleation status of the cell. RNA sequencing and subsequent bioinformatic analyses were carried out to investigate transcriptional changes induced by exercise specifically in aged hearts in comparison to young hearts. Cardiomyogenesis was observed at a significantly higher frequency in exercised compared with sedentary aged hearts based on the detection of mononucleated/diploid 15N-thymidine labeled cardiomyocytes. No mononucleated/diploid 15N-thymidine labeled cardiomyocyte was detected in sedentary aged mice. The annual rate of mononucleated/diploid 15N-thymidine labeled cardiomyocytes in aged, exercised mice was 2.3% per year. This compares to our previously reported annual rate of 7.5% in young, exercised mice and 1.63% in young, sedentary mice. Transcriptional profiling of young and aged exercised murine hearts and their sedentary controls revealed that exercise induces pathways related to circadian rhythm, irrespective of age. One known oscillating transcript, however, that was exclusively upregulated in aged, exercised hearts, was RCAN1.4, whose regulation and functional role were explored further. Our data demonstrate that voluntary running partially restores cardiomyogenesis in aged mice and suggest that pathways associated with circadian rhythm may play a role in physiologically stimulated cardiomyogenesis.