How to repair a damaged heart: Key mechanism behind heart regeneration in zebrafish revealed
IMAGE: ZEBRAFISH HEART 60 DAYS AFTER INJURY SHOWING THE STRUCTURE OF THE HEART MUSCLE CELLS HAVE COMPLETELY REGENERATED. view more
CREDIT: CREDIT: PHONG NGUYEN, COPYRIGHT HUBRECHT INSTITUTE.
Cardiovascular diseases, such as heart attacks, are a leading cause of death worldwide resulting from a limited self-healing power of the heart. Unlike humans, zebrafish have the remarkable capacity to recover from cardiac damage. Researchers from the group of Jeroen Bakkers (Hubrecht Institute) have used the zebrafish to shed light on their regenerative success. They discovered a new mechanism that functions as a switch to push the heart muscle cells to mature in the regeneration process. Importantly, this mechanism was evolutionary conserved as it had a very similar effect on mouse and human heart muscle cells. The results of the study, published in Science on May 18th, show that examining the natural heart regeneration process in zebrafish and applying these discoveries to human heart muscle cells could contribute to the development of new therapies against cardiovascular diseases.
It is estimated that 18 million people die from cardiovascular diseases every year. Many of these deaths are related to heart attacks. In such an event, a blood clot prevents the supply of nutrients and oxygen to parts of the heart. As a result, the heart muscle cells in the obstructed part of the heart die, which eventually leads to heart failure. Although therapies exist that manage the symptoms, there is no treatment that is able to replace the lost tissue with functional, mature heart muscle cells and thereby cure the patients.
Zebrafish as a role model
Unlike humans, some species like zebrafish can regenerate their hearts. Within 90 days after damage, they fully restore their cardiac function. The surviving heart muscle cells are able to divide and produce more cells. This unique feature provides zebrafish hearts with a source of new tissue to replace the lost heart muscle cells. Previous studies successfully identified factors that could stimulate heart muscle cells to divide. Nevertheless, what happens to the newly formed heart muscle cells afterwards had not been studied before. Phong Nguyen, first author of the study, explains: “It is unclear how these cells stop dividing and mature enough so that can they contribute to normal heart function. We were puzzled by the fact that in zebrafish hearts, the newly formed tissue naturally matured and integrated into the existing heart tissue without any problems.”.
LRRC10 drives maturation
To study maturation of the newly formed tissue in detail, the researchers developed a technique for which thick slices of injured zebrafish hearts were cultured outside the body. This allowed them to perform live imaging on the movement of calcium in heart muscle cells. The regulation of calcium moving in and out of heart muscle cells is important for controlling heart contractions and can predict the maturity of the cell. They found that after the heart muscle cells divide, calcium movements changed over time. “The calcium movement in the newly divided cell was initially very similar to embryonic heart muscle cells, but over time the heart muscle cells assumed a mature type of calcium movement. We found that the cardiac dyad, a structure that helped to move calcium within the heart muscle cell, and specifically one of its components, LRRC10, was crucial in deciding whether heart muscle cells divide or progress through maturation. Heart muscle cells that lack LRRC10 continued to divide and remained immature,” says Nguyen.
From fish to human
After Nguyen and his colleagues established the importance of LRRC10 in stopping cell division and initiating maturation of zebrafish heart muscle cells, they moved on to test if their findings could be translated to mammals. To this end, they induced the expression of LRRC10 in mouse and lab-grown human heart muscle cells. Strikingly, LRRC10 changed the calcium handling, reduced cell division and increased the maturation of these cells in a similar manner as observed in zebrafish hearts. Nguyen: “It was exciting to see that the lessons learned from the zebrafish were translatable as this opens new possibilities for the use of LRRC10 in the context of new therapies for patients”.
Clinical impact
The results of the study, published in Science, show that LRRC10 has the potential to drive the maturation of heart muscle cells further through the control of their calcium handling. This could help scientists who are trying to solve the lack of regenerative capacity of the mammalian heart by transplanting lab-grown heart muscle cells into the damaged heart. Although this potential therapy is promising, results showed that these lab-grown cells are still immature and cannot communicate properly with the rest of the heart, leading to abnormal contractions called arrhythmias. “Although more research is needed to precisely define how mature these lab-grown heart muscle cells are when treated with LRRC10, it is possible that the increase in maturation will improve their integration after transplantation,” says Jeroen Bakkers, last author of the study. Bakkers continues: “Additionally, current models for cardiac diseases are frequently based on immature lab-grown heart muscle cells. 90% of promising drug candidates found in the lab fail to make it to the clinic and the immaturity of these cells could be one contributing factor for this low success rate. Our results indicate LRRC10 could improve the relevance of these models as well”. LRRC10 could thus have an important contribution to generate lab-grown heart muscle cells that more accurately represent a typical adult human heart, therefore improving the chances of developing successful new treatments against cardiovascular diseases.
Publication
Interplay between calcium and sarcomeres directs cardiomyocyte maturation during regeneration. Phong D. Nguyen*, Iris Gooijers†, Giulia Campostrini†, Arie O. Verkerk, Hessel Honkoop, Mara Bouwman, Dennis E. M. de Bakker, Tim Koopmans, Aryan Vink, Gerda E. M. Lamers, Avraham Shakked, Jonas Mars, Aat A. Mulder, Sonja Chocron, Kerstin Bartscherer, Eldad Tzahor, Christine L. Mummery, Teun P. de Boer, Milena Bellin, Jeroen Bakkers*. Science, 2023.
The study is the result of a collaboration between the Hubrecht Institute, LUMC, AMC, UMC Utrecht and Weizmann Institute. The study was financed with the help of the Dutch Heart Foundation, Dutch CardioVascular Alliance and Stichting Hartekind.
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Jeroen Bakkers is group leader at the Hubrecht Institute and professor of Molecular Cardiogenetics at the UMC Utrecht
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About the Hubrecht Institute
The Hubrecht Institute is a research institute focused on developmental and stem cell biology. Because of the dynamic character of the research, the institute as a variable number of research group, around 20, that do fundamental, multidisciplinary research on healthy and diseased cells, tissues and organisms. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht, advancing the translation of research to the clinic. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL). For more information, visit www.hubrecht.eu.
JOURNAL
Science
DOI
African Killifish could hold secrets to reversing muscle ageing
New research in the African killifish reveals that towards the end of life, our muscles actually reverse to an “early-life” state, clues to preventing muscle wasting
Peer-Reviewed PublicationIMAGE: A JUST-HATCHED KILLIFISH LARVAE STAINED WITH ANTIBODIES AGAINST MYOSIN (RED), ACTININ (GREEN) AND COLLAGEN (BLUE). view more
CREDIT: DR AVNIKA RUPARELIA
As we age, our muscles start to waste. Called sarcopenia, it happens to us all, yet no one has ever understood why and how it happens. Now new research from the Australian Regenerative Medicine Institute (ARMI) at Monash University has used a surprising animal model – the African killifish – to reveal that towards the end of life, our muscles actually reverse to an “early-life” state, slowing mortality. This finding may provide a clue to slowing, halting or even reversing age-related loss of muscle mass and strength.
The research, published in the Aging Cell and led by Professor Peter Currie and Dr Avnika Ruparelia, who is from ARMI and the University of Melbourne, is important because of the expected dramatic increase in the prevalence and severity of sarcopenia throughout the global population.
According to Professor Currie, “…there is a pressing need to understand the mechanisms that drive sarcopenia, so that we can identify and implement suitable medical interventions to promote healthy muscle ageing,” he said.
The African turquoise killifish, Nothobranchius furzeri has recently emerged as a new model for the study of ageing. Killifish have the shortest known life span of any vertebrate species that can be bred in captivity. Life for a killifish begins with the African rains, creating seasonal rain pools in which fish hatch, grow rapidly and mature in as few as two weeks, and then reproduce daily until the pool dries out.
Importantly, their short life span is accompanied with symptoms of ageing we see in humans – including the appearance of cancerous lesions in the liver and gonads, reduced regenerative capacity of the limbs, in this case the fin, and genetic characteristics that are the hallmark of human ageing such as a reduction in mitochondrial DNA copy number and function and shortening of telomeres.
According to Dr Ruparelia, this study is the first to use the killifish to study sarcopenia.
“In this study, we performed a thorough cellular and molecular characterization of skeletal muscle from early life, aged and extremely old late-life stages, revealing many similarities to sarcopenia in humans and other mammals,” she said.
Surprisingly the researchers also found these same metabolic hallmarks of ageing are reversed during the late-life stage, “suggesting that in extremely old animals, there may be
mechanisms in place that prevent further deterioration of skeletal muscle health, which may ultimately contribute to an extension of their life span,” Dr Ruparelia said.
“Importantly, the late-life stage during which we observed improved muscle health perfectly coincides with a stage when mortality rates decline. We therefore postulate that the improvement in muscle health may be a critical factor contributing to the extension of life span in extremely old individuals.”
To better understand the mechanisms behind this, the research team surveyed the metabolism of fish at different stages of the ageing process. This experiment surprisingly revealed that certain features of the metabolism of the very oldest fish actually were rejuvenated to resemble those of young fish. It highlighted the critical role of lipid metabolism in this process of rejuvenation. By using drugs that regulate the formation of certain lipids a similar rejuvenation of ageing muscle could be achieved.
“During extreme old age, there is a striking depletion of lipids, which are the main energy reserves in our cells,” explains senior author Prof Currie.
“We believe that this mimics a state of calorie restriction, a process known to extend life span in other organsims, which results in activation of downstream mechanisms ultimately enabling the animal to maintain nutrient balance and live longer. A similar process is seen in the muscle of highly trained athletes.”
Dr Ruparelia went on to say, “The idea that muscle ageing may be reversible, and potentially treatable by drugs that can manipulate a cell’s metabolism, is an exciting prospect especially given the social, economic and healthcare costs associated with the ever-growing aged population around the world. We are excited by the potential of the killifish model, and very grateful to the Winston Churchill Trust for funding, and to Hon Dr Kay Patterson for her assistance with establishing the import regulations to establish first and only killifish facility in Australia. We now have a unique opportunity to study biological processes regulating ageing and age-related diseases, and to investigate strategies to promote heathy ageing.”
The publication was the cumulation of a collaboration between researchers from:
- Australian Regenerative Medicine Institute (Australia)
- Monash Biomedicine Discovery Institute (Australia)
- The University of Melbourne (Australia)
- Centre for Muscle Research (Australia)
- Peter MacCallum Cancer Centre (Australia)
- Leibniz Institute on Aging – Fritz Lipmann Institute (Germany)
More information
The Currie group is curious about the biological mechanisms of the zebrafish, a freshwater fish that is native to South-East Asia. Zebrafish are used in scientific research to understand human genetics and the biological processes of human diseases. For more information on Professor Peter Currie and his group at ARMI, please visit the Currie Group page. You can contact Dr Avnika Ruparelia or Professor Peter Currie via avnika.ruparelia@unimelb.edu.au and peter.currie@monash.edu respectively.
JOURNAL
Aging Cell
METHOD OF RESEARCH
Observational study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
The African killifish: A short-lived vertebrate model to study the biology of sarcopenia and longevity
ARTICLE PUBLICATION DATE
16-May-2023
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
Interplay between calcium and sarcomeres directs cardiomyocyte maturation during regeneration
ARTICLE PUBLICATION DATE
19-May-2023
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