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Exercise reduces calcineurin activity in aged hearts, and RCAN1.4 overexpression in aged cardiomyocytes increases cardiomyocyte cell cycle markers. A, The fraction of NFATc1 positive cardiomyocyte nuclei per section area (%) was quantified in aged mouse hearts. Exercise treatment reduced NFATc1 expression in cardiomyocyte nuclei, compared with sedentary control hearts (n=4 mice/group, **P<0.001, Student t-test). B, Representative images from aged sedentary and exercised mouse hearts show NFATc1 (red) stained nuclei (DAPI, blue), in combination with wheat germ agglutinin (WGA, green). Scale bar, 100 μm. C, Validation of cell cycle regulators Cdca2 and Ccnd1 mRNA expression in aged sedentary and exercised mouse hearts (n=8 mice/group, *P<0.05, **P<0.01, Student t-test). D, Isolated murine aged cardiomyocytes (20 months) were infected with RCAN1.1 (AdV-RCAN1.1) and RCAN1.4 (AdV-RCAN1.4) and LacZ control (AdV-LacZ) adenoviruses, respectively, and Cdc2a and Ccnd1 mRNA expression was analyzed (n=3-6 replicates per treatment from a total of 6 hearts, *P<0.05, 1-way ANOVA). E, NRVM were infected with RCAN1.1 (AdV-RCAN1.1) and RCAN1.4 (AdV-RCAN1.4) and LacZ control (AdV-LacZ) adenoviruses, respectively, and Ccnd1 mRNA expression was analyzed after stimulation with indicated serum concentrations (n=4, *P<0.05, **P<0.01, ***P<0.001, 2-way ANOVA). F, NRVM were infected with RCAN1.1 (AdV-RCAN1.1) and RCAN1.4 (AdV-RCAN1.4) and LacZ control (AdV-LacZ) adenoviruses, (Continued )
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Background:
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...
Contexts in source publication
Context 1
... used immunofluorescence staining to determine endogenous nuclear localization of NFATc1 in cardiomyocytes from aged exercised and sedentary hearts. We found significantly reduced NFATc1 nuclear staining in aged exercised hearts compared with aged sedentary hearts, indicating reduced calcineurin activity with exercise ( Figure 6A and 6B). These findings confirm a role for the calcineurin-NFAT signaling axis for myocardial adaptation to exercise in aged hearts. ...
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... proliferation in other tissues, for example, in the liver or malignant diseases such as colorectal cancer, by activating cyclin D1 (Ccnd1). 18 We confirmed upregulated Cdc2a in aged exercised hearts, and also found increased Ccnd1 expression in these tissues compared with aged sedentary hearts, suggesting a role for cell cycle regulators in our model as well ( Figure 6C). We next sought to test whether adenoviral overexpression of either Rcan1.1 or Rcan1.4 stimulates cardiomyocyte cell cycle activity in isolated murine aged cardiomyocytes. ...
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... next sought to test whether adenoviral overexpression of either Rcan1.1 or Rcan1.4 stimulates cardiomyocyte cell cycle activity in isolated murine aged cardiomyocytes. We found that both Cdc2a and Ccnd1 expression were increased specifically by adenoviral Rcan1.4 expression ( Figure 6D). We confirmed sufficient and specific adenoviral (multiplicity of infection 50) overexpression of RCAN1.1 and RCAN1.4 protein in cultured neonatal rat ventricular myocytes (NRVM; Figure S3A). ...
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... RCAN1.1 expression showed significantly decreased Ccnd1 expression compared with both LacZ control and RCAN1.4-treated cells, suggesting (as in isolated aged cardiomyocytes) isotype-specific regulation of cell cycle in NRVM ( Figure 6E). As depicted in Figure S3A, a similar pattern was detected when analyzing protein expression of the mitosis marker pHH3 (phospho-histone-H3) in RCAN1.1/1.4 ...
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... similar increase in Ki67 staining with serum stimulation in RCAN1.1/1.4 NRVM was detected when compared with control LacZ NRVM, in the absence of increased cell counts, further suggesting that RCAN1 overexpression in NRVM did not lead to increased cardiomyocyte cytokinesis during the observed time (Fig- ure 6G and 6H). In summary, our data show that RCAN1.4 is sufficient to stimulate cardiomyocyte cell cycle activity in aged cardiomyocytes in vitro, suggesting a particular susceptibility to RCAN1-calcineurin signaling. ...
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... Determining the rate of cardiomyocyte renewal in adult hearts is technically challenging. The technique applied in the present study is reliably and unambiguously able to determine the rate of cardiomyogenesis per time period by combining quantitative isotope-based Figure 6 Continued. respectively, and pHH3 (phospho-Histone-H3) protein expression was analyzed after stimulation with indicated serum concentrations (n=4, *P<0.05, ...
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... The reduced running activity of aged animals may contribute to the lower absolute number of new cardiomyocytes in exercised aged hearts. However, post hoc analysis of the correlation of 15 N-positive cardiomyocytes to the distance run in young exercised cohorts we previously reported 10 did not reveal a linear relationship, suggesting that the critical difference may not be attributable to less distance run ( Figure S6). It is important to mention, however, that our previous project was not designed to answer that question specifically, the sample size is small, and a threshold effect cannot be fully excluded, which is why this research question will be given specific attention in future projects. ...
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Citations
... Physical activity promotes healthy aging and prevents CVD [162][163][164][165] . Progressive and vigorous exercise for 1 year in previously sedentary people aged 65 and over induces physiological LV remodeling, increases stroke volume and total aortic compliance, and decreases arterial elastance [166] , while studies in aged mice correlated the benefits of exercise with increased exercise capacity, improved diastolic function, physiological cardiac hypertrophy and increased cardiomyogenesis [167][168][169] . Even in mice expressing a proofreading-deficient version of Polg, endurance exercise for 5 months increases mitochondrial biogenesis and mitochondrial oxidative capacity and alleviates age-associated cardiomyopathy [170] . ...
Progressive age-induced deterioration in the structure and function of the cardiovascular system involves cardiac hypertrophy, diastolic dysfunction, myocardial fibrosis, arterial stiffness, and endothelial dysfunction. These changes are driven by complex processes that are interconnected, such as oxidative stress, mitochondrial dysfunction, autophagy, inflammation, fibrosis, and telomere dysfunction. In recent years, the advances in research of cardiovascular aging, including the wide use of animal models of cardiovascular aging, elucidated an abundance of cell signaling pathways involved in these processes and brought into sight possible interventions, which span from pharmacological agents, such as metformin, sodium-glucose cotransporter 2-inhibitors, rapamycin, dasatinib and quercetin, to lifestyle changes.
... In addition to the above-mentioned cells in the heart, the cardiac rhythm cells have an irreplaceable role in maintaining the normal operation of the heart. Lerchenmüller et al. reported that exercise can induce cardiac regeneration and pathways related to circadian rhythm in mice (63). Although the evidence is limited on relations between myocardial regeneration and cardiac rhythmic cells after revascularization, it can be expected that circadian rhythm plays a crucial role in cardiac regeneration. ...
Coronary chronic total occlusion (CTO) contributes to the progression of heart failure in patients with ischemic cardiomyopathy. Randomized controlled trials demonstrated that percutaneous coronary intervention (PCI) for CTO significantly improves angina symptoms and quality of life but fails to reduce clinical events compared with optimal medical therapy. Even so, intervening physicians strongly support CTO-PCI. Cardiac regeneration therapy after CTO-PCI should be a promising approach to improving the prognosis of ischemic cardiomyopathy. However, the relationship between CTO revascularization and cardiac regeneration has rarely been studied, and experimental studies on cardiac regeneration usually employ rodent models with permanent ligation of the coronary artery rather than reopening of the occlusive artery. Limited early-stage clinical trials demonstrated that cell therapy for cardiac regeneration in ischemic cardiomyopathy reduces scar size, reverses cardiac remodeling, and promotes angiogenesis. This review focuses on the status quo of CTO-PCI in ischemic cardiomyopathy and the clinical prospect of cardiac regeneration in this setting.
Cardiovascular disease (CVD) has become a severe threat to human health, with morbidity and mortality increasing yearly and gradually becoming younger. When the disease progresses to the middle and late stages, the loss of a large number of cardiomyocytes is irreparable to the body itself, and clinical drug therapy and mechanical support therapy cannot reverse the development of the disease. To explore the source of regenerated myocardium in model animals with the ability of heart regeneration through lineage tracing and other methods, and develop a new alternative therapy for CVDs, namely cell therapy. It directly compensates for cardiomyocyte proliferation through adult stem cell differentiation or cell reprogramming, which indirectly promotes cardiomyocyte proliferation through non-cardiomyocyte paracrine, to play a role in heart repair and regeneration. This review comprehensively summarizes the origin of newly generated cardiomyocytes, the research progress of cardiac regeneration based on cell therapy, the opportunity and development of cardiac regeneration in the context of bioengineering, and the clinical application of cell therapy in ischemic diseases.
Significance:
Heart failure is often accompanied by a decrease in the number of cardiomyocytes. Although the adult mammalian hearts have limited regenerative capacity, the rate of regeneration is extremely low and decreases with age. Exercise is an effective mean to improve cardiovascular function and prevent cardiovascular diseases. However, the molecular mechanisms of how exercise acts on cardiomyocytes are still not fully elucidated. Therefore, it is important to explore the role of exercise in cardiomyocytes and cardiac regeneration.
Recent advances:
Recent advances have shown that the effects of exercise on cardiomyocytes are critical for cardiac repair and regeneration. Exercise can induce cardiomyocytes growth by increasing the size and number. It can induce physiological cardiomyocytes hypertrophy, inhibit cardiomyocytes apoptosis, and promote cardiomyocytes proliferation. In this review, we have discussed the molecular mechanisms and recent studies of exercise-induced cardiac regeneration, with a focus on its effects on cardiomyocytes.
Critical issues:
There is no effective way to promote cardiac regeneration. Moderate exercise can keep the heart healthy by encouraging adult cardiomyocytes to survive and regenerate. Therefore, exercise could be a promising tool for stimulating the regenerative capability of the heart and keeping the heart healthy.
Future directions:
Although exercise is an important measure to promote cardiomyocytes growth and subsequent cardiac regeneration, more studies are needed on how to do beneficial exercise and what factors are involved in cardiac repair and regeneration. Thus, it is important to clarify the mechanisms, pathways, and other critical factors involved in the exercise-mediated cardiac repair and regeneration.
Cardiometabolic diseases still represent a major cause of mortality worldwide. In addition to pharmacological approaches, lifestyle interventions can also be adopted for the prevention of these morbid conditions. Lifestyle changes include exercise and dietary restriction protocols, such as calorie restriction and intermittent fasting, which were shown to delay cardiovascular ageing and elicit health-promoting effects in preclinical models of cardiometabolic diseases. Beneficial effects are mediated by the restoration of multiple molecular mechanisms in heart and vessels that are compromised by metabolic stress. Exercise and dietary restriction rescue mitochondrial dysfunction, oxidative stress and inflammation. They also improve autophagy. The result of these effects is a marked improvement of vascular and heart function. In this review, we provide a comprehensive overview of the molecular mechanisms involved in the beneficial effects of exercise and dietary restriction in models of diabetes and obesity. We also discuss clinical studies and gap in animal-to-human translation.
Exercise benefits the whole organism, yet, how tissues across the body orchestrally respond to exercise remains enigmatic. Here, in young and old mice, with or without exercise, and exposed to infectious injury, we characterized the phenotypic and molecular adaptations to 12-month exercise across 14 tissues/organs at single-cell resolution. Overall, exercise protects tissues from infectious injury, although more effectively in young animals, and benefits aged individuals in terms of inflammaging suppression and tissue rejuvenation, with structural improvement in the central nervous system and systemic vasculature being most prominent. In vascular endothelial cells, we found that readjusting the rhythmic machinery via the core circadian clock protein BMAL1 delayed senescence and facilitated recovery from infectious damage, recapitulating the beneficial effects of exercise. Our study underscores the effect of exercise in reconstituting the youthful circadian clock network and provides a foundation for further investigating the interplay between exercise, aging, and immune challenges across the whole organism.
Cardiomyocytes comprise ∼70% to 85% of the total volume of the adult mammalian heart but only about 25% to 35% of its total number of cells. Advances in single cell (sc) and single nuclei (sn) RNA sequencing (scRNA-seq and snRNA-seq) have greatly facilitated investigation into and increased appreciation of the potential functions of non-cardiomyocytes in the heart. While much of this work has focused on the relationship between non-cardiomyocytes, disease, and the heart's response to pathological stress, it will also be important to understand the roles that these cells play in the healthy heart, cardiac homeostasis, and the response to physiological stress such as exercise.
The present review summarizes recent research highlighting dynamic changes in non-cardiomyocytes in response to the physiological stress of exercise. Of particular interest are changes in fibrotic pathways, the cardiac vasculature, and immune or inflammatory cells. In many instances, limited data are available about how specific lineages change in response to exercise or whether the changes observed are functionally important, underscoring the need for further research.
