scholarly journals Exercise, programmed cell death and exhaustion of cardiomyocyte proliferation in aging zebrafish

2021 ◽  
Author(s):  
Lindsay B. Murphy ◽  
Adrian Santos-Ledo ◽  
Tamilvendhan Dhanaseelan ◽  
Lorraine Eley ◽  
David Burns ◽  
...  
Keyword(s):  
Cell Death ◽  
Proliferative Response ◽  
Physiological Stress ◽  
Cardiovascular Fitness ◽  
Cardiac Insufficiency ◽  
Laboratory Model ◽  
Cardiomyocyte Proliferation ◽  
Cardiovascular Performance ◽  
Old Adult ◽  
Zebrafish Heart

As the human heart ages, the myocardium undergoes fibrotic remodelling, there is declining cardiovascular performance and eventual heart failure. It is suggested that exercise is an important intervention to ameliorate these changes. In this study we establish zebrafish as a laboratory model to understand how aging and exercise affect cardiomyocyte turnover. We show the zebrafish heart does not exhibit indeterminate growth but follows the pattern seen in human aging. In zebrafish, cardiomyocyte proliferation remains constant, but a late increase cell death underlies the pattern of initial cardiac growth and later fibrosis. These anatomical findings are corelated with the human like decline in cardiovascular performance reflected in voluntary swimming activity, critical swimming speed (Ucrit) and biomarkers of cardiac insufficiency. Whilst the vertebrate heart can respond to injury through cardiomyocyte proliferation, it is not known if a proliferative response occurs when the cardiovascular system is exposed to prolonged severe physiological stress, or if this changes with age. To investigate this, young and old adult zebrafish were challenged by 72 hours of enforced swimming in a purpose-built flume at levels close to maximal Ucrit. Whilst young adult fish produced a significant proliferative response older fish had a dramatically impaired response, provided by a smaller proliferative cardiomyocyte population. Finally, we asked if these aging responses could be improved by increased activity throughout adulthood. Whilst there was some improvement in the aged proliferative response the size of the reduced proliferative cardiomyocyte pool remained unchanged and importantly, there was increased myocardial fibrosis. The zebrafish heart thus provides a laboratory model to study cardiomyocyte turnover during aging and physiological stresses, revealing the important trade-off between preserving cardiovascular fitness through exercise and accelerated fibrotic change, whilst the available proliferative pool of cardiomyocytes continues to diminish.

scholarly journals CDK9 and its repressor LARP7 modulate cardiomyocyte proliferation and response to injury in the zebrafish heart

2015 ◽  
Vol 128 (24) ◽  
pp. 4560-4571 ◽  
Author(s):  
G. Matrone ◽  
K. S. Wilson ◽  
S. Maqsood ◽  
J. J. Mullins ◽  
C. S. Tucker ◽  
...  
Keyword(s):  
Cardiomyocyte Proliferation ◽  
Zebrafish Heart

scholarly journals Correction: Igf Signaling is Required for Cardiomyocyte Proliferation during Zebrafish Heart Development and Regeneration

PLoS ONE ◽  
2014 ◽  
Vol 9 (1) ◽  
Author(s):  
Ying Huang ◽  
Michael R. Harrison ◽  
Arthela Osorio ◽  
Jieun Kim ◽  
Aaron Baugh ◽  
...  
Keyword(s):  
Heart Development ◽  
Cardiomyocyte Proliferation ◽  
Zebrafish Heart ◽  
Igf Signaling

HYPERTROPHY AND HYPERPLASIA IN THE MOUSE UTERUS AFTER OESTROGEN TREATMENT: AN AUTORADIOGRAPHIC STUDY

1973 ◽  
Vol 56 (1) ◽  
pp. 133-NP ◽  
Author(s):  
L. MARTIN ◽  
C. A. FINN ◽  
GAIL TRINDER
Keyword(s):  
Cell Death ◽  
Dna Synthesis ◽  
Proliferative Response ◽  
Autoradiographic Study ◽  
Luminal Epithelium ◽  
Uterine Tissue ◽  
Mouse Uterus ◽  
Oestrogen Treatment ◽  
Ovariectomized Mice

SUMMARY The uteri of untreated ovariectomized mice consisted almost entirely of myometrium and connective tissue stroma. After oestrogenic stimulation these tissues underwent marked hypertrophy, but showed little proliferation. The luminal epithelium underwent marked hyperplasia, with most cells dividing twice to quadruple cell numbers by 35–40 h, when they made up 10–12% of the uterine tissue volume and 20% of the total uterine cell population. The proliferative response was rapid, highly synchronized and short-lived. The number of cells incorporating [3H]thymidine first increased 8·5 h after oestradiol-17β and by 13–16 h 60–70% were engaged in DNA synthesis. Up to 21 h cell-death was minimal. From 21 h onwards the proliferation rate declined and the rate of cell death increased. A second injection of oestrogen prevented the rise in death rate and produced a second smaller burst of DNA synthesis. Cells in DNA synthesis or mitosis were insensitive to oestrogen. A smaller proliferative response occurred in the glands: only 25% of cells entered DNA synthesis after the first injection of oestradiol and none after the second. Gland cells appeared to die in situ and there was no evidence that they migrated into the luminal epithelium.

Cardiomyocyte proliferation in cardiac development and regeneration: a guide to methodologies and interpretations

2015 ◽  
Vol 309 (8) ◽  
pp. H1237-H1250 ◽  
Author(s):  
Marina Leone ◽  
Ajit Magadum ◽  
Felix B. Engel
Keyword(s):  
Cardiac Function ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Cardiac Regeneration ◽  
Experimental Medicine ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Naturally Occurring ◽  
Ability To Regenerate ◽  
Zebrafish Heart

The newt and the zebrafish have the ability to regenerate many of their tissues and organs including the heart. Thus, a major goal in experimental medicine is to elucidate the molecular mechanisms underlying the regenerative capacity of these species. A wide variety of experiments have demonstrated that naturally occurring heart regeneration relies on cardiomyocyte proliferation. Thus, major efforts have been invested to induce proliferation of mammalian cardiomyocytes in order to improve cardiac function after injury or to protect the heart from further functional deterioration. In this review, we describe and analyze methods currently used to evaluate cardiomyocyte proliferation. In addition, we summarize the literature on naturally occurring heart regeneration. Our analysis highlights that newt and zebrafish heart regeneration relies on factors that are also utilized in cardiomyocyte proliferation during mammalian fetal development. Most of these factors have, however, failed to induce adult mammalian cardiomyocyte proliferation. Finally, our analysis of mammalian neonatal heart regeneration indicates experiments that could resolve conflicting results in the literature, such as binucleation assays and clonal analysis. Collectively, cardiac regeneration based on cardiomyocyte proliferation is a promising approach for improving adult human cardiac function after injury, but it is important to elucidate the mechanisms arresting mammalian cardiomyocyte proliferation after birth and to utilize better assays to determine formation of new muscle mass.

The zebrafish as a model for cardiac development and regeneration

2018 ◽  
Author(s):  
Bill Chaudhry ◽  
José Luis de la Pompa ◽  
Nadia Mercader
Keyword(s):  
Heart Development ◽  
Cardiac Development ◽  
Model Organism ◽  
Laboratory Model ◽  
Developmental Studies ◽  
Sequencing Technologies ◽  
Technological Advances ◽  
The Common ◽  
Zebrafish Heart

The zebrafish has become an established laboratory model for developmental studies and is increasingly used to model aspects of human development and disease. However, reviewers and grant funding bodies continue to speculate on the utility of this Himalayan minnow. In this chapter we explain the similarities and differences between the heart from this distantly related vertebrate and the mammalian heart, in order to reveal the common fundamental processes and to prevent misleading extrapolations. We provide an overview of zebrafish including their husbandry, development, peculiarities of their genome, and technological advances, which make them a highly tractable laboratory model for heart development and disease. We discuss the controversies around morphants and mutants, and relate the development and structures of the zebrafish heart to mammalian counterparts. Finally, we give an overview of regeneration in the zebrafish heart and speculate on the role of the model organism in next-generation sequencing technologies.

scholarly journals Delineating the Dynamic Transcriptome Response of mRNA and microRNA during Zebrafish Heart Regeneration

Biomolecules ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 11 ◽  
Author(s):  
Hagen Klett ◽  
Lonny Jürgensen ◽  
Patrick Most ◽  
Martin Busch ◽  
Fabian Günther ◽  
...  
Keyword(s):  
Heart Function ◽  
Heart Diseases ◽  
Expression Profiles ◽  
Temporal Organization ◽  
H9c2 Cell ◽  
Specific Response ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Transcriptome Response ◽  
Zebrafish Heart

Heart diseases are the leading cause of death for the vast majority of people around the world, which is often due to the limited capability of human cardiac regeneration. In contrast, zebrafish have the capacity to fully regenerate their hearts after cardiac injury. Understanding and activating these mechanisms would improve health in patients suffering from long-term consequences of ischemia. Therefore, we monitored the dynamic transcriptome response of both mRNA and microRNA in zebrafish at 1–160 days post cryoinjury (dpi). Using a control model of sham-operated and healthy fish, we extracted the regeneration specific response and further delineated the spatio-temporal organization of regeneration processes such as cell cycle and heart function. In addition, we identified novel (miR-148/152, miR-218b and miR-19) and previously known microRNAs among the top regulators of heart regeneration by using theoretically predicted target sites and correlation of expression profiles from both mRNA and microRNA. In a cross-species effort, we validated our findings in the dynamic process of rat myoblasts differentiating into cardiomyocytes-like cells (H9c2 cell line). Concluding, we elucidated different phases of transcriptomic responses during zebrafish heart regeneration. Furthermore, microRNAs showed to be important regulators in cardiomyocyte proliferation over time.

scholarly journals Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Matthew Gemberling ◽  
Ravi Karra ◽  
Amy L Dickson ◽  
Kenneth D Poss
Keyword(s):  
Cardiac Injury ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Adult Zebrafish ◽  
Perivascular Cells ◽  
Adult Heart ◽  
Muscle Hyperplasia ◽  
Zebrafish Heart

Heart regeneration is limited in adult mammals but occurs naturally in adult zebrafish through the activation of cardiomyocyte division. Several components of the cardiac injury microenvironment have been identified, yet no factor on its own is known to stimulate overt myocardial hyperplasia in a mature, uninjured animal. In this study, we find evidence that Neuregulin1 (Nrg1), previously shown to have mitogenic effects on mammalian cardiomyocytes, is sharply induced in perivascular cells after injury to the adult zebrafish heart. Inhibition of Erbb2, an Nrg1 co-receptor, disrupts cardiomyocyte proliferation in response to injury, whereas myocardial Nrg1 overexpression enhances this proliferation. In uninjured zebrafish, the reactivation of Nrg1 expression induces cardiomyocyte dedifferentiation, overt muscle hyperplasia, epicardial activation, increased vascularization, and causes cardiomegaly through persistent addition of wall myocardium. Our findings identify Nrg1 as a potent, induced mitogen for the endogenous adult heart regeneration program.

scholarly journals Igf Signaling is Required for Cardiomyocyte Proliferation during Zebrafish Heart Development and Regeneration

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e67266 ◽  
Author(s):  
Ying Huang ◽  
Michael R. Harrison ◽  
Arthela Osorio ◽  
Jieun Kim ◽  
Aaron Baugh ◽  
...  
Keyword(s):  
Heart Development ◽  
Cardiomyocyte Proliferation ◽  
Zebrafish Heart ◽  
Igf Signaling

scholarly journals CDK9 and its repressor LARP7 modulate cardiomyocyte proliferation and response to injury in the zebrafish heart

Development ◽  
2016 ◽  
Vol 143 (1) ◽  
pp. e1.2-e1.2
Author(s):  
Gianfranco Matrone ◽  
Kathryn S. Wilson ◽  
Sana Maqsood ◽  
John J. Mullins ◽  
Carl S. Tucker ◽  
...  
Keyword(s):  
Cardiomyocyte Proliferation ◽  
Zebrafish Heart
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