A metabolic switch from OXPHOS to glycolysis is essential for cardiomyocyte proliferation in the regenerating heart
Posted on: 30 January 2019 , updated on: 31 January 2019
Preprint posted on 18 December 2018
Article now published in eLife at http://dx.doi.org/10.7554/eLife.50163
Heart regeneration: Cardiomyocytes need to undergo a metabolic switch in order to re-enter the cell cycle
Selected by Andreas van Impel
Categories: cell biology, developmental biology
Background
During myocardial infarctions the occlusion of a blood vessel leads to an undersupply of oxygen in the cardiac muscle tissue, resulting in the loss of heart muscle cells. After such cardiac injuries the mammalian heart fails to replace the ischemic areas with novel functional contractile cardiomyocytes. This inability to regenerate results in cardiac dysfunction and often even in heart failure which makes heart attacks a major cause of death in humans.
In contrasts to mammals, fish and amphibians possess remarkable regenerative properties which have made these animals important models for regeneration in general and heart regeneration in particular. Previous work has shown that upon injury of the zebrafish heart cardiomyocyte proliferation is induced in the so-called border zone area surrounding the affected tissue; this ultimately results in the complete replacement of the apoptotic cardiomyocytes within the injury area by novel functional heart muscle cells [reviewed in 1]. However, it is currently not fully understood which processes and signalling events drive this regenerative response in the zebrafish heart (in contrast to the responses induced in mammalian cardiac tissues).
Key findings
In order to more closely characterize the small number of differentiated cardiomyocytes that start to re-enter the cell cycle after heart injury, Honkoop, de Bakker and colleagues performed single cell mRNA-sequencing on border zone tissue isolated from cryo-injured adult zebrafish hearts. Subsequent transcriptome analysis revealed that cardiomyocytes cluster into four different subgroups with normal, adult cardiomyocytes in one cluster and dedifferentiated, embryonic-like cardiomyocytes expressing various known border zone marker genes in a separate cluster. The remaining two subgroups reflect intermediated populations of dedifferentiating cardiomyocytes. Further analysis indicated that many genes involved in energy producing metabolic pathways were differentially expressed among the individual clusters, implicating fundamental metabolic changes in cardiomyocytes during their dedifferentiation and re-entry into the cell cycle. In particular, differentiated, adult cardiomyocytes show increased expression of genes involved in the oxygen-dependent mitochondrial oxidative phosphorylation while the proliferative population within the border zone seemed to have increased expression of enzymes required for glycolysis accompanied by a reduction in mitochondrial activity.
To test the functional importance of this finding, the authors inhibited glycolysis and found that under these conditions cardiomyocyte proliferation in the border zone was significantly reduced, suggesting that the proposed metabolic switch during the dedifferentiation of cardiomyocytes is involved in cell cycle re-entry and therefore the regeneration of heart tissue. Furthermore, the authors show that Neuregulin1, a potent injury-induced mitogen that is known to trigger cardiomyocyte dedifferentiation [2], acts upstream of this metabolic switch as it induces the expression of glycolysis genes in cardiomyocytes. Finally, the authors turn to a murine model with an improved cardiac regenerative capacity (mice overexpressing the Neuregulin1 receptor ErbB2) to address the importance of increased glycolysis for cardiomyocyte proliferation and heart regeneration in the mammalian system. As one would predict from the zebrafish results, Honkoop, de Bakker et al. find that ErbB2 overexpressing mice (in contrast to wild type mice) show an enhanced expression of glycolysis related genes in cardiomyocytes after myocardial infarction and that this induction is essential for their cell cycle re-entry and therefore the increased heart regeneration in this mouse model. Taken together, the here presented results demonstrate that cardiomyocytes undergo an important metabolic reprogramming (from mitochondrial oxidative phosphorylation to increased glycolysis) during the response to cardiac injury, which is essential for the induction of cell proliferation and the regeneration of cardiac tissue.
Why this is cool
The preprint from the Bakkers lab nicely demonstrates the power of single cell transcriptomics in identifying and characterizing cellular responses and events in relatively small subpopulations of a certain cell type, which might otherwise get masked in the transcriptome analysis of a mixture of the whole cell population. Using this approach, the authors find an essential role for a shift in the energy providing metabolic pathways during the induction of cardiomyocyte proliferation and heart regeneration. The here presented results therefore imply that this metabolic cardiomyocyte reprogramming represents another important piece of the ‘heart regeneration puzzle’ and that an induction of such a switch might provide a promising target for therapeutic interventions after myocardial infarction in the future.
Open questions / future directions
- Do all cardiomyocytes in the border zone initiate or at least have the capacity to undergo this metabolic switch and to re-enter the cell cycle? If not, what makes this dedifferentiating population special?
- What is the exact molecular connection between enhanced glycolysis and cardiomyocyte dedifferentiation / induction of proliferation?
- Is a ‘reverse metabolic switch’ required to end the regeneration program in cardiomyocytes?
- How can one stimulate such a metabolic switch after myocardial infarction in human patients and would that alone be sufficient for an improved prognosis?
Further reading
[1] González‐Rosa, J. M., Burns, C. E., Burns, C. G. Zebrafish heart regeneration: 15 years of discoveries. Regeneration (Oxf). 2017 Jun; 4(3): 105–123
[2] Gemberling, M., Karra, R., Dickson, A. L., Poss, K. D. Nrg1 is an injuryinduced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish. eLife 2015;4:e05871
doi: https://doi.org/10.1242/prelights.8010
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