Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression

Abstract

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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Fig. 1: Dietary fatty acid deficiency from birth results in a pronounced prolongation of the postnatal window of cardiomyocyte proliferation.
Fig. 2: Chronic exposure to fat-free diet induces liver steatosis in adult mice.
Fig. 3: Conditional PDK4 deletion results in a marked shift in myocardial substrate utilization, decreased DNA damage and increased proliferation in adult cardiomyocytes.
Fig. 4: PDK4-KO hearts show a higher LVEF accompanied by a remarkable decrease in LV dilatation and remodelling, as well as increased cardiomyocyte proliferation, compared with control hearts.

Data availability

RNA-seq raw data have been deposited in the NCBI Sequence Read Archive (SRA) database with accession number PRJNA593900. Source Data for Figs. 3 and 4 and Extended Data Fig. 4 are available online.

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Acknowledgements

H. I. May (Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA) for the myocardial infarction surgeries in mice. H.A.S. is supported by grants from the NIH (1R01HL115275 and 5R01H2131778), National Aeronautics and Space Administration (NNX-15AE06G), American Heart Association (16EIA27740034), Cancer Prevention and Research Institute of Texas (RP160520), Hamon Center for Regenerative Science and Medicine and Fondation Leducq. N.T.L. is supported by a Haberecht Wildhare-Idea Research Grant. A.D.S. is supported by grant from the NIH (R37-HL034557), C.R.M. is supported by grant from the NIH (P41-EB015908) and G.S. is supported by the grant from the AHA (18POST34050049). M.K. is supported by the grants from NIH (3P20GM103447 and 5P30AG050911). I.M.M. is supported by Alfonso Martin Escudero Foundation Fellowship. N.U.N.N. is supported by AHA Postdoctoral Fellowship 19POST34450039. J.A.H. is supported by grants from the NIH (HL-120732, HL-128215 and HL-126012).

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A.C.C. and N.T.L. performed the experiments. A.C.C, N.T.L. and H.A.S. designed the experiments, performed the analyses and wrote the manuscript. J.J.S. contributed to writing and manuscript preparation. J.J.S. and S.L. performed the echocardiography. A.E. and L.I.S. performed PDH activity analysis. G.V., K.M.E., M.A.M. and J.G.M. performed the lipidomics experiments. Y.N., S.A. and A.A. performed the DNA-damage experiments. I.M.M., L.H. and P.W.S performed the lipid serum profile experiments. G.S., A.D.S., C.R.M. and C.K. performed the NMR experiments. M.T.K. performed the proteomics data. W.L.W.T., C.G.A.N. and R.S.Y.F. performed the RNA-seq. C.X. and M.K. contributed to the bioinformatics analysis. A.H.M.P., N.U.N.N., M.S.A. and W.M.E contributed and performed the experiments in mice. A.H.M.P., E.L.E and U.B.P. contributed to the experimental design and performed the experiments in mice. J.A.H. contributed to experimental design in mice. L.I.S. and H.A.S. conceived the project and contributed to manuscript preparation.

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Correspondence to Alisson C. Cardoso or Hesham A. Sadek.

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Extended data

Extended Data Fig. 1 Quantitative mass spectrometry analysis of fatty acids biosynthesis liver enzymes.

a, Schematic view of cholesterol and triglyceride biosynthesis pathways. Red, green and gray colors represent the upregulated, downregulated and unchanged protein expression, respectively. The analysis shows a significant increase in the enzymes involved in the synthesis of saturated fatty acids and triglycerides in FDM compare to CM mice. Enzymes involved in cholesterol biosynthesis were downregulated in the FDM liver. b, Table showing the average, fold change and p-value of the hepatic enzymes involved in fatty acid biosynthesis, identified by quantitative mass spectrometry between FDM and CM mice (n=4 biologically independent mice per group). CM, control milk group; FDM, fat deficient milk group. Statistical analysis was performed with two-tailed Student’s t-test.

Extended Data Fig. 2 Serum lipids and blood glucose measurements.

a, At 12 days postnatally, beyond lactation, pups were exposed to a regular diet or Fat Free Diet. Samples were collected at 10 weeks postnatally. Data in b-f represent the blood glucose, total cholesterol, triglycerides, HDL cholesterol or LDL cholesterol measurements, respectively. (n=7 biologically independent mice per group) Data presented as the mean ± s.e.m. Statistical analysis was analyzed with two-tailed Student’s t-test.

Extended Data Fig. 3 RNA-seq analysis of PDK4 KO and Control hearts.

a, Heat-map of all dysregulated genes. Yellow and blue colors represent upregulated and downregulated genes, respectively (n=5 biologically independent mice for control and n=4 biologically independent mice for PDK4 KO group). b, Scatter plot showing the Fragments Per Kilobase of transcript, per Million mapped reads (FPKM) in control and PDK4 KO group (n=5 biologically independent mice for control and n=4 biologically independent mice for PDK4 KO). c, Volcano plot of the log of fold change dysregulated genes between Control and PDK4 KO group. (n=5 biologically independent mice for control and n=4 biologically independent mice for PDK4 KO). Statistic analysis was performed by two-tailed F-test for differential gene expression analysis. d, Ontology analysis performed using DAVID Functional Annotation Tool. Statistics analysis was performed by hypergeometric test. e, heat maps showing a number of dysregulated pathways, including DNA replication, lipid metabolic process, carbohydrate metabolic process, cell cycle and cell growth. Red and green colors represent upregulated and downregulated genes, respectively (n=5 biologically independent mice for control and n=4 biologically independent mice for PDK4 KO). CT: Control.

Extended Data Fig. 4 Timeline of PDK4 deletion in the inducible model.

Western blot of PDK4 shows elimination of the protein as early as 4 days following the first tamoxifen injection. Source data

Extended Data Fig. 5 Echocardiography parameters.

a, left ventricular internal dimension in diastole (LVIDd); b, left ventricular internal dimension in systole (LVIDs), echocardiogram measurements, comparing PDK4 KO and the control αMHC-MerCreMer (MCM) at different time points (n=5 biologically independent mice per group). Data are represented as the mean ± s.d. Analyses were performed by unpaired two-tailed Student’s t-test to compare MCM vs PDK4 KO. Paired two-tailed Student’s t-test was used to compare two time points within the same mouse (6 months post MI versus 1 week post MI). c, LVDd; d, LVIDs echocardiogram measurements, comparing uninjured versus myocardial infarction (MI) MCM and PDK4 KO groups (n=4 biologically independent mice for uninjured and n=5 biologically independent mice for MI groups). Data are represented as the mean ± s.e.m. Analyses were performed by Two-way ANOVA followed by Tukey’s multiple comparisons test, with individual variance computed for each comparison. ns, not significant. e, Trichrome staining of control MCM and PDK4 KO uninjured hearts, 6 months post Tamoxifen injection. Images are representative of three independently performed experiments, with similar results.

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Source data

Source Data Fig. 3

Unprocessed western blot referent to figure 3

Source Data Fig. 4

Unprocessed western blot referent to figure 4

Source Data Fig. Extended Data Fig. 4

Unprocessed western blot referent to extended data fig. 4

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Cardoso, A.C., Lam, N.T., Savla, J.J. et al. Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression. Nat Metab 2, 167–178 (2020). https://doi.org/10.1038/s42255-020-0169-x

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