Periodic Reporting for period 4 - TransReg (Transgenerational epigenetic inheritance of cardiac regenerative capacity in the zebrafish)
Reporting period: 2024-02-01 to 2025-07-31
While myocardial infarction leads to adverse ventricular remodeling ultimately causing heart failure in humans, some animals, including zebrafish can regenerate the injured heart. For regeneration to occur, cardiac muscle cells in the zebrafish can repopulate the lost heart muscle. For this they can enter cell division and afterwards re-acquire their contractile functions. TransReg aimed to understand if all cardiomyocytes have the same capacity to contribute to heart regeneration. Furthermore, we wondered if a memory of an injury is retained in the tissue or whole organism that could influence future injuries. We were particularly interested in understanding if a cardiac injury memory persists from one generation to the next and, if that is the case, it this could influence regenerative capacity of offspring.
Unravelling the mechanisms that allow natural heart regeneration in some species could inspire the development of regenerative therapies for humans. Also, knowing if and how experiences affecting health can be transmitted to subsequent generations is of relevance for the understanding of disease.
Unravelling the mechanisms that allow natural heart regeneration in some species could inspire the development of regenerative therapies for humans. Also, knowing if and how experiences affecting health can be transmitted to subsequent generations is of relevance for the understanding of disease.
We analyzed which are the mechanisms driving the plasticity of heart muscle cells to re-enter cell division, a prerequisite of heart regeneration. We found that within mitochondria, the supramolecular organization of the respiratory chain dictates to some extent the regenerative capacity of cardiac muscle cells to respond to injury with entry into the cell cycle.
The findings are of interest as they provide a possible targeting route to transiently manipulate the ability of cardiac muscle cells to divide. This can in the future be exploited by the identification of small molecules inhibiting the specific respiratory complex assembly.
Cox7a1 controls skeletal muscle physiology and heart regeneration through complex IV dimerization.
García-Poyatos C, Arora P, Calvo E, Marques IJ, Kirschke N, Galardi-Castilla M, Lembke C, Meer M, Fernández-Montes P, Ernst A, Haberthür D, Hlushchuk R, Vázquez J, Vermathen P, Enríquez JA, Mercader N.Dev Cell. 2024 Jul 22;59(14):1824-1841.e10. doi: 10.1016/j.devcel.2024.04.012.
A second main finding from this ERC project comes from the study of the effect of a parental cardiac lesion on offspring. We were able to identify that in mice there is intergenerational inheritance of a neonatal cardiac lesion from one generation to the next. Pups from males with a cardiac cryolesion revealed alterations in cardiac function in the neonatal period and physiological alterations suggesting a better recovery after cardiac injury.
Our results, that need further validation in other models, suggests non-genetic inheritance of an experience across one generation in mammals.
Cox7a1 controls skeletal muscle physiology and heart regeneration through complex IV dimerization.
García-Poyatos C, Arora P, Calvo E, Marques IJ, Kirschke N, Galardi-Castilla M, Lembke C, Meer M, Fernández-Montes P, Ernst A, Haberthür D, Hlushchuk R, Vázquez J, Vermathen P, Enríquez JA, Mercader N.Dev Cell. 2024 Jul 22;59(14):1824-1841.e10. doi: 10.1016/j.devcel.2024.04.012.
The findings are of interest as they provide a possible targeting route to transiently manipulate the ability of cardiac muscle cells to divide. This can in the future be exploited by the identification of small molecules inhibiting the specific respiratory complex assembly.
Cox7a1 controls skeletal muscle physiology and heart regeneration through complex IV dimerization.
García-Poyatos C, Arora P, Calvo E, Marques IJ, Kirschke N, Galardi-Castilla M, Lembke C, Meer M, Fernández-Montes P, Ernst A, Haberthür D, Hlushchuk R, Vázquez J, Vermathen P, Enríquez JA, Mercader N.Dev Cell. 2024 Jul 22;59(14):1824-1841.e10. doi: 10.1016/j.devcel.2024.04.012.
A second main finding from this ERC project comes from the study of the effect of a parental cardiac lesion on offspring. We were able to identify that in mice there is intergenerational inheritance of a neonatal cardiac lesion from one generation to the next. Pups from males with a cardiac cryolesion revealed alterations in cardiac function in the neonatal period and physiological alterations suggesting a better recovery after cardiac injury.
Our results, that need further validation in other models, suggests non-genetic inheritance of an experience across one generation in mammals.
Cox7a1 controls skeletal muscle physiology and heart regeneration through complex IV dimerization.
García-Poyatos C, Arora P, Calvo E, Marques IJ, Kirschke N, Galardi-Castilla M, Lembke C, Meer M, Fernández-Montes P, Ernst A, Haberthür D, Hlushchuk R, Vázquez J, Vermathen P, Enríquez JA, Mercader N.Dev Cell. 2024 Jul 22;59(14):1824-1841.e10. doi: 10.1016/j.devcel.2024.04.012.
With our studies we aim to understand whether a cardiac injury in a parental generation can influence the regenerative capacity of subsequent generations.