TY - JOUR
T1 - Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression
AU - Cardoso, Alisson C.
AU - Lam, Nicholas T.
AU - Savla, Jainy J.
AU - Nakada, Yuji
AU - Pereira, Ana Helena M.
AU - Elnwasany, Abdallah
AU - Menendez-Montes, Ivan
AU - Ensley, Emily L.
AU - Bezan Petric, Ursa
AU - Sharma, Gaurav
AU - Sherry, A. Dean
AU - Malloy, Craig R.
AU - Khemtong, Chalermchai
AU - Kinter, Michael T.
AU - Tan, Wilson Lek Wen
AU - Anene-Nzelu, Chukwuemeka G.
AU - Foo, Roger Sik Yin
AU - Nguyen, Ngoc Uyen Nhi
AU - Li, Shujuan
AU - Ahmed, Mahmoud Salama
AU - Elhelaly, Waleed M.
AU - Abdisalaam, Salim
AU - Asaithamby, Aroumougame
AU - Xing, Chao
AU - Kanchwala, Mohammed
AU - Vale, Gonçalo
AU - Eckert, Kaitlyn M.
AU - Mitsche, Matthew A.
AU - McDonald, Jeffrey G.
AU - Hill, Joseph A.
AU - Huang, Linzhang
AU - Shaul, Philip W.
AU - Szweda, Luke I.
AU - Sadek, Hesham A.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - The neonatal mammalian heart is capable of regeneration for a brief window of time after birth. However, this regenerative capacity is lost within the first week of life, which coincides with a postnatal shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty-acid utilization. Despite the energy advantage of fatty-acid beta-oxidation, cardiac mitochondria produce elevated rates of reactive oxygen species when utilizing fatty acids, which is thought to play a role in cardiomyocyte cell-cycle arrest through induction of DNA damage and activation of DNA-damage response (DDR) pathway. Here we show that inhibiting fatty-acid utilization promotes cardiomyocyte proliferation in the postnatal heart. First, neonatal mice fed fatty-acid-deficient milk showed prolongation of the postnatal cardiomyocyte proliferative window; however, cell-cycle arrest eventually ensued. Next, we generated a tamoxifen-inducible cardiomyocyte-specific pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse model to selectively enhance oxidation of glycolytically derived pyruvate in cardiomyocytes. Conditional PDK4 deletion resulted in an increase in pyruvate dehydrogenase activity and consequently an increase in glucose relative to fatty-acid oxidation. Loss of PDK4 also resulted in decreased cardiomyocyte size, decreased DNA damage and expression of DDR markers and an increase in cardiomyocyte proliferation. Following myocardial infarction, inducible deletion of PDK4 improved left ventricular function and decreased remodelling. Collectively, inhibition of fatty-acid utilization in cardiomyocytes promotes proliferation, and may be a viable target for cardiac regenerative therapies.
AB - The neonatal mammalian heart is capable of regeneration for a brief window of time after birth. However, this regenerative capacity is lost within the first week of life, which coincides with a postnatal shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation, particularly towards fatty-acid utilization. Despite the energy advantage of fatty-acid beta-oxidation, cardiac mitochondria produce elevated rates of reactive oxygen species when utilizing fatty acids, which is thought to play a role in cardiomyocyte cell-cycle arrest through induction of DNA damage and activation of DNA-damage response (DDR) pathway. Here we show that inhibiting fatty-acid utilization promotes cardiomyocyte proliferation in the postnatal heart. First, neonatal mice fed fatty-acid-deficient milk showed prolongation of the postnatal cardiomyocyte proliferative window; however, cell-cycle arrest eventually ensued. Next, we generated a tamoxifen-inducible cardiomyocyte-specific pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse model to selectively enhance oxidation of glycolytically derived pyruvate in cardiomyocytes. Conditional PDK4 deletion resulted in an increase in pyruvate dehydrogenase activity and consequently an increase in glucose relative to fatty-acid oxidation. Loss of PDK4 also resulted in decreased cardiomyocyte size, decreased DNA damage and expression of DDR markers and an increase in cardiomyocyte proliferation. Following myocardial infarction, inducible deletion of PDK4 improved left ventricular function and decreased remodelling. Collectively, inhibition of fatty-acid utilization in cardiomyocytes promotes proliferation, and may be a viable target for cardiac regenerative therapies.
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U2 - 10.1038/s42255-020-0169-x
DO - 10.1038/s42255-020-0169-x
M3 - Article
C2 - 32617517
AN - SCOPUS:85079802946
SN - 2522-5812
VL - 2
SP - 167
EP - 178
JO - Nature Metabolism
JF - Nature Metabolism
IS - 2
ER -