Stimulation of glycolysis promotes cardiomyocyte proliferation after injury in adult zebrafish

Abstract

Cardiac metabolism plays a crucial role in producing sufficient energy to sustain cardiac function. However, the role of metabolism in different aspects of cardiomyocyte regeneration remains unclear. Working with the adult zebrafish heart regeneration model, we first find an increase in the levels of mRNAs encoding enzymes regulating glucose and pyruvate metabolism, including pyruvate kinase M1/2 (Pkm) and pyruvate dehydrogenase kinases (Pdks), especially in tissues bordering the damaged area. We further find that impaired glycolysis decreases the number of proliferating cardiomyocytes following injury. These observations are supported by analyses using loss-of-function models for the metabolic regulators Pkma2 and peroxisome proliferator-activated receptor gamma coactivator 1 alpha. Cardiomyocyte-specific loss-and gain-of-function manipulations of pyruvate metabolism using Pdk3 as well as a catalytic subunit of the pyruvate dehydrogenase complex (PDC) reveal its importance in cardiomyocyte dedifferentiation and proliferation after injury. Furthermore, we find that PDK activity can modulate cell cycle progression and protrusive activity in mammalian cardiomyocytes in culture. Our findings reveal new roles for cardiac metabolism and the PDK-PDC axis in cardiomyocyte behavior following cardiac injury.

Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration

“… 24 , 92 Recent studies have revealed that pyruvate dehydrogenase kinase (PDK) regulates glycolysis and pyruvate metabolism of cardiomyocytes of the border area in zebrafish after injury. 93 Moreover, the loss of PDK4 can increase the proliferation of cardiomyocytes and improve left ventricular function after MI and reduce remodeling. 94 These findings suggest that energy metabolism plays a critical role in cardiomyocyte proliferation after injury.…”

Transcriptional Regulation of Postnatal Cardiomyocyte Maturation and Regeneration

“…Fetal cardiomyocyte energy production occurs primarily by glycolysis in rodents, although there is evidence of mid-to-late gestational onset of oxidative metabolic pathways in some large mammals, such as sheep [ 28 ]. In zebrafish hearts, increased glycolysis and pyruvate metabolism is noted in cardiomyocyte proliferation and regenerative repair of the heart [ 29 ]. In rodent hearts, cardiomyocyte metabolism undergoes rapid transition from glycolytic to fatty acid oxidation in the first few days after birth with postnatal increase in oxygen consumption [ 30 ].…”

“…Human and pig mitochondrial dynamics during heart development are not well-characterized, but, given the shared atmospheric oxygen environment between these species and rodents, along with the incidence of human neonatal mitochondrial cardiomyopathies associated with oxidative phosphorylation defects [ 36 , 37 , 38 ], it is likely that a similar mitochondrial maturation occurs in large mammal cardiomyocytes. In the regenerative adult zebrafish model, the state of the mitochondria more closely resembles that of the neonatal mouse, with increased glycolysis and pyruvate metabolism noted in proliferative cardiomyocytes and regenerative repair of the heart [ 29 ]. These data support a link between the extent of mitochondrial maturation and cardiomyocyte proliferative capacity in the heart.…”

Cardiac regenerative capacity: an evolutionary afterthought?

“…Indeed, a recent study has shown that the transcriptome of zebrafish border zone CMs is more similar to embryonic CMs then to remote myocardial CMs originating from the same hearts [88]. This reversion back to an embryonic state is likely key to unlock their proliferative potential as inhibiting their dedifferentiation, including the induction of glycolysis, prevents CMs from proliferating effectively [86][87][88][89].…”