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Voluntary wheel running induces physiological cardiac adaptation in aged mice. Echocardiographic analysis showed preserved fractional shortening (FS) (A), with increased anterior and posterior wall thickness (B) in systole and diastole (LVAWs/d, LVPWs/d) in exercised aged animals compared with aged sedentary controls (n=7-11 mice/group, ****P<0.0001, ***P=0.0001, **P=0.0081, Student t-test). C, Both heart weight to tibia length (HW/TL) and heart weight to body weight (HW/BW) ratios were increased in exercised aged mice (n=11-15 mice/group, HW/TL ****P<0.0001, HW/BW ***P=0.0007 Student t-test). D, Likewise, cardiomyocyte cross-sectional area analyzed from wheat germ-agglutinin-stained transverse left ventricular sections showed an increase in cardiomyocyte size with exercise (>100 cardiomyocytes were counted per group, n=4 mice/group, *P<0.05, Student t-test). E, Anticipated switch of α/β-myosin heavy chain gene (MHC) expression after 8 weeks of voluntary wheel running was also detected. PGC1-α was downregulated after 8 weeks (n=5 mice/group, *P<0.05, Student t-test). F, Running activity (running distance per 24 hours) was measured for each mouse for 8 weeks. Aged mice ran on average 2.4 km per 24 hours (n=4 mice/group). All data are presented as mean±SEM. ANP indicates atrial natriuretic peptide; BNP, brain natriuretic peptide; CEBP, CCAAT/enhancer binding protein; CITED, Cbp/p300-interacting transactivator 4; HIPK, homeodomaininteracting protein kinase; PGC, 1α-peroxisome proliferator-activated receptor gamma coactivator 1-alpha; and SED, sedentary.
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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...
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... systolic function (ie, fractional shortening) was not changed after 8 weeks of voluntary wheel running when assessed by echocardiography in aged exercised animals compared with sedentary controls ( Figure 1A), suggesting the absence of maladaptive cardiac remodeling. However, in previous studies investigating the exercise response of young animals, a mild exercise-induced increase in fractional shortening was observed. ...
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... in previous studies investigating the exercise response of young animals, a mild exercise-induced increase in fractional shortening was observed. 10,14 Echocardiographic imaging also revealed an increase in left ventricular (LV) posterior wall thickness and septal wall thickness ( Figure 1B) in mice subjected to voluntary running indicative of exercise-induced hypertrophic LV remodeling. Cardiac weight normalized to tibial length or body weight after 8 weeks of voluntary wheel running supported the echocardiographic data, showing increased heart weights ( Figure 1C) and cardiomyocyte hypertrophy (cross-sectional area; Figure 1D) in exercised mice compared with sedentary mice. ...
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... Echocardiographic imaging also revealed an increase in left ventricular (LV) posterior wall thickness and septal wall thickness ( Figure 1B) in mice subjected to voluntary running indicative of exercise-induced hypertrophic LV remodeling. Cardiac weight normalized to tibial length or body weight after 8 weeks of voluntary wheel running supported the echocardiographic data, showing increased heart weights ( Figure 1C) and cardiomyocyte hypertrophy (cross-sectional area; Figure 1D) in exercised mice compared with sedentary mice. In addition, gene expression analysis showed typical changes indicating physiological cardiac remodeling, for example, decreased β-myosin heavy chain expression accompanied with a ≈2-fold increase in α-myosin heavy chain to β-myosin heavy chain ratio without differences in atrial natriuretic peptide/brain natriuretic peptide expression ( Figure 1E). ...
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... Echocardiographic imaging also revealed an increase in left ventricular (LV) posterior wall thickness and septal wall thickness ( Figure 1B) in mice subjected to voluntary running indicative of exercise-induced hypertrophic LV remodeling. Cardiac weight normalized to tibial length or body weight after 8 weeks of voluntary wheel running supported the echocardiographic data, showing increased heart weights ( Figure 1C) and cardiomyocyte hypertrophy (cross-sectional area; Figure 1D) in exercised mice compared with sedentary mice. In addition, gene expression analysis showed typical changes indicating physiological cardiac remodeling, for example, decreased β-myosin heavy chain expression accompanied with a ≈2-fold increase in α-myosin heavy chain to β-myosin heavy chain ratio without differences in atrial natriuretic peptide/brain natriuretic peptide expression ( Figure 1E). ...
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... weight normalized to tibial length or body weight after 8 weeks of voluntary wheel running supported the echocardiographic data, showing increased heart weights ( Figure 1C) and cardiomyocyte hypertrophy (cross-sectional area; Figure 1D) in exercised mice compared with sedentary mice. In addition, gene expression analysis showed typical changes indicating physiological cardiac remodeling, for example, decreased β-myosin heavy chain expression accompanied with a ≈2-fold increase in α-myosin heavy chain to β-myosin heavy chain ratio without differences in atrial natriuretic peptide/brain natriuretic peptide expression ( Figure 1E). Unlike in young mice, in which exercise induces differential expression of CEBP/β (CCAAT/enhancer binding protein), CITED4 (Cbp/p300-interacting transactivator 4), PGC1α (1α-peroxisome proliferator-activated receptor gamma coactivator 1-alpha), and microRNA 222 targets HIPK1 and HIPK2 (homeodomain-interacting protein kinase), among others, we did not observe these changes in aged exercised mice, suggesting that exercise may induce physiological hypertrophic changes through different mechanisms in the aged heart (Fig- ure 1E). ...
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... addition, gene expression analysis showed typical changes indicating physiological cardiac remodeling, for example, decreased β-myosin heavy chain expression accompanied with a ≈2-fold increase in α-myosin heavy chain to β-myosin heavy chain ratio without differences in atrial natriuretic peptide/brain natriuretic peptide expression ( Figure 1E). Unlike in young mice, in which exercise induces differential expression of CEBP/β (CCAAT/enhancer binding protein), CITED4 (Cbp/p300-interacting transactivator 4), PGC1α (1α-peroxisome proliferator-activated receptor gamma coactivator 1-alpha), and microRNA 222 targets HIPK1 and HIPK2 (homeodomain-interacting protein kinase), among others, we did not observe these changes in aged exercised mice, suggesting that exercise may induce physiological hypertrophic changes through different mechanisms in the aged heart (Fig- ure 1E). Aged mice provided with a running wheel for 8 weeks ran 2.4 km/24 h on average ( Figure 1F). ...
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... in young mice, in which exercise induces differential expression of CEBP/β (CCAAT/enhancer binding protein), CITED4 (Cbp/p300-interacting transactivator 4), PGC1α (1α-peroxisome proliferator-activated receptor gamma coactivator 1-alpha), and microRNA 222 targets HIPK1 and HIPK2 (homeodomain-interacting protein kinase), among others, we did not observe these changes in aged exercised mice, suggesting that exercise may induce physiological hypertrophic changes through different mechanisms in the aged heart (Fig- ure 1E). Aged mice provided with a running wheel for 8 weeks ran 2.4 km/24 h on average ( Figure 1F). We previously reported that young mice from the same strain ran 5.57 km/24 hours on average when subjected to the voluntary wheel running protocol, 10 demonstrating a decline in voluntary running with age. ...
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... next isolated cardiomyocytes and noncardiomyocytes from young and aged hearts to determine the primary expression pattern of Rcan1 in the heart. Pure isolation was confirmed by mRNA expression of Troponin T (Tnnt, mostly expressed in cardiomyocytes, Figure S1A) and expression of Collagen 1a (Col1α, mostly expressed in fibroblasts, Figure S1B). We could confirm that both Rcan1.1 ( Figure 5B) and Rcan1.4 ( Figure 5C) were predominantly expressed Nuclear localization of NFAT can therefore be used as an indirect measure of calcineurin activity. ...
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... next isolated cardiomyocytes and noncardiomyocytes from young and aged hearts to determine the primary expression pattern of Rcan1 in the heart. Pure isolation was confirmed by mRNA expression of Troponin T (Tnnt, mostly expressed in cardiomyocytes, Figure S1A) and expression of Collagen 1a (Col1α, mostly expressed in fibroblasts, Figure S1B). We could confirm that both Rcan1.1 ( Figure 5B) and Rcan1.4 ( Figure 5C) were predominantly expressed Nuclear localization of NFAT can therefore be used as an indirect measure of calcineurin activity. ...
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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.
