Department of Cardiology, University Hospital Heidelberg, Germany (C.L., S.M., C.P.R., C.H., F.B., A.Y.R., N.F., C.D.).
German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany (C.L., S.M., F.B., N.F., C.D.).
Circulation. 2022 Aug 2;146(5):412-426. doi: 10.1161/CIRCULATIONAHA.121.057276. Epub 2022 Jul 6.
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 still unknown. Here, we aim to investigate the effect of exercise on the generation of new cardiomyocytes in the aged heart.
Aged (20-month-old) mice were subjected to an 8-week voluntary running protocol, and age-matched sedentary animals served as controls. Cardiomyogenesis in aged hearts was assessed on the basis of N-thymidine incorporation and multi-isotope imaging mass spectrometry. We analyzed 1793 cardiomyocytes from 5 aged sedentary mice and compared these with 2002 cardiomyocytes from 5 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 performed to investigate transcriptional changes induced by exercise specifically in aged hearts in comparison with young hearts.
Cardiomyogenesis was observed at a significantly higher frequency in exercised compared with sedentary aged hearts on the basis of the detection of mononucleated/diploid N-thymidine-labeled cardiomyocytes. No mononucleated/diploid N-thymidine-labeled cardiomyocyte was detected in sedentary aged mice. The annual rate of mononucleated/diploid N-thymidine-labeled cardiomyocytes in aged exercised mice was 2.3% per year. This compares with 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 isoform 1.4 of regulator of calcineurin, whose regulation and functional role were explored further.
Our data demonstrate that voluntary running in part restores cardiomyogenesis in aged mice and suggest that pathways associated with circadian rhythm may play a role in physiologically stimulated cardiomyogenesis.
人类心脏生成新心肌细胞的能力有限，这种能力会随着年龄的增长而下降。由于心肌细胞的丢失可能导致心力衰竭，因此探索内源性心脏再生的刺激因素，有利于在老年心脏中使心肌细胞的丢失和新生之间达到平衡，这一点至关重要。我们之前已经证明，运动可以激活年轻成年小鼠心脏中的心肌发生。然而，运动是否也能诱导老年心脏中的心肌发生，目前尚不清楚。在这里，我们旨在研究运动对老年心脏中新心肌细胞生成的影响。
将老年（20 月龄）小鼠进行 8 周的自愿跑步方案，将年龄匹配的久坐不动的动物作为对照。基于 N-胸腺嘧啶核苷掺入和多同位素成像质谱分析，评估老年心脏中的心肌发生情况。我们分析了 5 只老年久坐不动的小鼠的 1793 个心肌细胞，并将这些数据与 5 只老年运动的小鼠的 2002 个心肌细胞进行了比较，随后进行了高级组织学和成像分析，以解释细胞的倍性和核形成状态。进行 RNA 测序和随后的生物信息学分析，以专门研究与年轻心脏相比，运动在老年心脏中诱导的转录变化。
与久坐不动的老年心脏相比，运动后的老年心脏中观察到更高频率的单核/二倍体 N-胸腺嘧啶核苷标记的心肌细胞。在久坐不动的老年小鼠中未检测到单核/二倍体 N-胸腺嘧啶核苷标记的心肌细胞。老年运动小鼠中单核/二倍体 N-胸腺嘧啶核苷标记的心肌细胞的年发生率为 2.3%。这与我们之前报道的年轻运动小鼠中的年发生率 7.5%和年轻久坐不动小鼠中的 1.63%相比有所降低。对年轻和老年运动小鼠心脏及其久坐不动对照的转录谱分析表明，运动诱导了与昼夜节律相关的途径，而与年龄无关。然而，有一种已知的振荡转录物，即钙调神经磷酸酶调节剂的同工型 1.4，仅在老年运动心脏中上调，其调节和功能作用进一步得到了探索。
我们的数据表明，自愿跑步部分恢复了老年小鼠的心肌发生，并表明与昼夜节律相关的途径可能在生理刺激的心肌发生中发挥作用。
