Abstract
The neonatal mammalian heart can regenerate following injury through cardiomyocyte proliferation but loses this potential by postnatal day 7. Stimulating adult cardiomyocytes to reenter the cell cycle remains unclear. Here we show that cardiomyocyte proliferation depends on its metabolic state. Given the connection between the tricarboxylic acid cycle and cell proliferation, we analyzed these metabolites in mouse hearts from postnatal day 0.5 to day 7 and found that α-ketoglutarate ranked highest among the decreased metabolites. Injection of α-ketoglutarate extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-ketoglutarate levels. Mechanistically, α-ketoglutarate decreases H3K27me3 deposition at the promoters of cell cycle genes in cardiomyocytes. Thus, α-ketoglutarate promotes cardiomyocyte proliferation through JMJD3-dependent demethylation, offering a potential approach for treating myocardial infarction.
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Acknowledgements
This work was supported, in part, by grants from the National Key Research and Development Program of China (2022YFA1104500) and National Natural Science Foundation of China (81930008, 82170288). Illustration items in the figures were created with BioRender.com.
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C.Z. conceived the study, designed the experiments and analyzed the data. Y.S. and C.Z. wrote the manuscript. P.A.J. edited the manuscript. Y.S., M.T. and X.Z. performed the immunofluorescence analysis. Y.S. and L.T. performed western blotting and real-time PCR and designed the animal models. Y.S. and M.T. performed ChIP–qPCR assay. Y.S. and F.W. performed the AAV9 viral studies. M.T., X.Z. and L.T. performed several experiments related to animal models. Y.S. and L.T. performed confocal imaging quantification and studies. Q.L. and F.W. evaluated the heart function. L.T. and Y.S. isolated and cultured the CMs. H.R. and S.Z. were responsible for breeding the mice. All authors approved the manuscript.
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Extended Data
Extended Data Fig. 1 Alterations of TCA metabolites in P0.5 and P7 mouse hearts.
a, Portrayal of differentially regulated TCA metabolites showing alterations of TCA metabolites in P0.5 and P7 mouse hearts. b, α-KG levels in cardiomyocytes isolated from P1, P7, P28 and P56 mice hearts (n = 5 hearts per group, *P < 0.05 vs. P1, #P < 0.05 vs. P7, &P < 0.05 vs. P28). c, Schematic diagram of the administration of α-KG in P7-P21 hearts. d, α-KG levels in lysates of cardiomyocytes isolated from hearts of P21 mice given α-KG (300 mg/kg daily from P7 to P21) (n = 6 hearts per group). Statistical analysis was evaluated using Two-way ANOVA with the Sidak’s multiple comparisons test in b; Two-tailed, unpaired Student t-tests in d. PBS was used as control. Values are mean ± SEM.
Extended Data Fig. 2 α-KG alleviates apoptosis and hypertrophy of cardiomyocytes.
a, Schematic diagram of the administration of α-KG and experimental approach in the MI mouse model. b, α-KG levels in cardiomyocytes dissociated from MI mice intraperitoneally injected with PBS or α-KG (300 mg/kg, daily for 2 weeks) (n = 5 hearts per group). c, Immunofluorescence images and quantification of CD31 immunostaining in heart sections, 14 days after MI (Top right of the main image: amplified area outlined in main image, Scale bar = 50 μm, n = 4 hearts per group). d, TUNEL staining together with cTnT and DAPI of mice hearts treated with PBS or α-KG at day14 post-MI (white arrows point to Tunel+/cTnT+, amplified area outlined in main image indicates typically stained CM, Scale bar = 50 μm, n = 5 hearts per group). e, Quantification of cardiomyocyte size by wheat germ agglutinin (WGA) staining in PBS- or α-KG-injected hearts at 28 days post-MI (Top right of the main image: amplified area outlined in main image, More than 200 cardiomyocytes per group, Scale bar = 50 μm, n = 5 hearts per group). f, Hematoxylin and Eosin (H&E) staining shows no significant morphological and pathological changes in tissue sections of indicated organs (n = 3 mice per group, Scale bar = 100 μm). Statistical analysis was evaluated using Two-tailed, unpaired Student t-tests in b, c, d; Two-way ANOVA with the Sidak’s multiple comparisons test in e. PBS was used as control. Values are mean ± SEM.
Extended Data Fig. 3 α-KG decreased the expression of maturation genes.
a, Heat maps showing differentially expressed genes associated with maturation. Red and blue colors represent upregulated and downregulated genes, respectively (n = 3 mice per group). b, α-KG treatment (5 mM, 48 h) down-regulates Atp2a2, Cacna1g, Tnni3, Myh6, Tpm1, Myl2, Jph2, and Ryr2 mRNA expressions in primary cultures of P1 cardiomyocytes (n = 4). Statistical analysis was evaluated using Two-tailed, unpaired Student t-tests. PBS was used as control. Values are mean ± SEM.
Extended Data Fig. 4 KYNA in α-KG-mediated cardiomyocyte proliferation.
a, Serum KYNA levels of mice given α-KG (300 mg/kg, 0.5 h after systemic α-KG administration) or PBS measured by ELISA (n = 4 mice per group). b, Schematic overview of the experimental approach and drug administration. c, Serum KYNA levels of MI mice that received the indicated treatments, measured by ELISA (n = 6 mice per group, NS, not significant). d, Cardiac function assessed by left ventricular ejection fraction (LVEF), LVFS, left ventricular internal diameter systolic (LVIDs), and left ventricular internal diameter diastolic (LVIDd) in adult mice treated with or without α-KG (300 mg/kg, 2 weeks) in the presence of the kynurenine aminotransferase (KAT) inhibitor, PF-04859989 (30 mg/kg) at 28-days post-MI in 8-week-old mice (n = 6 hearts per group, NS, not significant). e, Masson trichrome staining and fibrotic (scar) area quantification of heart sections from mice with or without α-KG (300 mg/kg, 2 weeks) treatment in the presence of KAT inhibitor, PF-04859989 (30 mg/kg) at day 28 post-MI (Scale bar = 1 mm, n = 5 hearts per group, NS, not significant). f, Immunostaining and quantification of Ki67+/cTnT+ or PH3+/cTnT+ cardiomyocytes at the border zone in hearts, post-MI, in 8-week-old mice with or without α-KG (300 mg/kg, 2 weeks) treatment in the presence of KAT inhibitor, PF-04859989 (100 mg/kg). (white arrows point to Ki67+cTnT+, PH3+cTnT+ cardiomyocytes, amplified area outlined in main image indicates typically stained CM, Scale bar = 20 μm, n = 5 hearts per group, NS, not significant). Statistical analysis was evaluated using Two-tailed, unpaired Student t-tests in a; One-way ANOVA with the Tukey’s multiple comparisons test in c-f. PBS was used as control. Values are mean ± SEM.
Extended Data Fig. 5 α-KG regulates H3K27me3, H3K4me3 and H3K27ac.
a, H3K27me3 chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) show a decreased enrichment of H3K27me3 on promoters of several cell cycle genes in cardiomyocytes isolated from P21 mice treated with α-KG (300 mg/kg/d for 2 weeks) (n = 3 hearts per group). b, Representative immunoblots and quantification of protein levels of H3K27me3 and H3K4me3 in P1 cardiomyocytes treated without (Control, PBS) or with α-KG (5 mM, 48 h) treatment (n = 5, n value refers to independent experiments). c, d, ChIP-qPCR analysis of H3K4me3 (c) and H3K27ac (d) enrichment on promoters of cell cycle (left figure) and maturation genes (right figure) in cultured cardiomyocytes supplemented with α-KG (5 mM, 48 h) compared with controls (n = 3, n value refers to independent experiments, NS, not significant). % of input is the normalized ChIP-qPCR signal relative to the input DNA. Statistical analysis was evaluated using Two-tailed, unpaired Student t-tests. PBS was used as control. Values are mean ± SEM. Uncropped blots for b are provided in Supplementary Source Data.
Extended Data Fig. 6 Administration of α-KG and GSK-J4 in mouse model of MI.
a, Immunostaining and quantification of Ki67+/cTnT+ in P1 cardiomyocytes with or without α-KG (5 mM, 48 h) treatment in the presence of Jmjd3 or Utx siRNA；Scramble was used as control (scale bar = 50 μm, n = 4, n value refers to independent experiments, white arrows show Ki67+/cTnT+ cardiomyocytes, NS, not significant). b, Representative immunoblots and quantification of protein levels of H3K27me3 in P1 cardiomyocytes treated without (Control, PBS) or with α-KG (5 mM, 48 h) in the presence of Jmjd3 or Utx siRNA; Scramble used as control (n = 6, n value refers to independent experiments, NS, not significant). c, Representative immunoblots and quantification of JMJD3 expression in P1 cardiomyocytes cultured with α-KG (5 mM, 48 h) or PBS (n = 6, n value refers to independent experiments). d, JMJD activity in nuclear extracts of P1 cardiomyocytes with or without α-KG (5 mM, 48 h) treatment (n = 5, n value refers to independent experiments). e, Schematic diagram of the administration of PBS (control), α-KG (300 mg/kg for 2 weeks), GSK-J4 (100 mg/kg for 2 weeks), a JMJD3 inhibitor, or α-KG + GSK-J4 in the MI mouse model. f, Representative immunoblots and quantification of JMJD3 expression in P1 cardiomyocytes at 2-days after Jmjd3 overexpression mediated by adenoviral delivery (n = 3, n value refers to independent experiments). Statistical analysis was evaluated using Two-tailed, unpaired Student t-tests in c, d and f; One-way ANOVA with the Tukey’s multiple comparisons test in a and b. Molecular weight marker (kDa) is shown. PBS was used as control. Values are mean ± SEM. Uncropped blots for b, c and f are provided in Supplementary Source Data.
Extended Data Fig. 7 α-KG induces amino acid synthesis in cardiomyocytes.
a, Volcano plot showing the most significantly altered metabolites in NRVMs treated with PBS, α-KG or si-Ogdh. α-KG group vs. Control group; si-Ogdh group vs. Control group. The X axis represents the (log2 (Fold Change)) of metabolites in different groups, and the Y axis represents the significance value of the difference (-log10(P value)). Each point represents a metabolite, red dots mean significantly up-regulated metabolites, and blue dots mean significantly down-regulated metabolites. b, Enrichment analysis of differentially regulated metabolites in NRVMs treated with scramble, α-KG or si-Ogdh showing the related metabolic processes. α-KG group vs. Control group; si-Ogdh group vs. Control group. c, d, Metabolites heatmap of tricarboxylic acid (TCA) cycle and amino acid metabolism in Control-, α-KG- and si-Ogdh- treated NRVMs. Heatmap denotes the metabolite signal intensities of each sample, showing significantly altered metabolites that increased or decreased in the α-KG or si-Ogdh group, compared with the Control group. e, f, Fold-changes of metabolites involved in TCA cycle and amino acid metabolism in NRVMs treated with scramble, α-KG or si-Ogdh (n = 4). Statistical analysis was evaluated using Fisher’s exact test in b; Two-tailed, unpaired Student t-tests in d and f. Scramble is used as control. Values are mean ± SEM.
Extended Data Fig. 8 Ogdh expression in hearts from P1 to P23 mice.
This analysis is based on a published study where untargeted metabolomics was performed on regenerative (P0.5) and non-regenerative (P7) mouse hearts. a, Heat map of mRNA and proteins that are involved in the regulation of α-KG metabolism. b, Violin plots of mRNA and proteins of Ogdh/OGDH in different stages of development from P1 to P23. c, Representative immunoblots and H3K27me3 quantification in cardiomyocytes isolated from mice at different stages of development from P1 to P23 (n = 3 hearts per group). d, Enzymatic activity of OGDH and isocitrate dehydrogenase (IDH) in cardiomyocytes isolated from mice at different stages of development from P1 to P23 (n = 4 hears per group). e, qRT–PCR results show the successful knockdown of Ogdh in P1 cardiomyocytes using Ogdh siRNA (n = 3, n value refers to independent experiments). f, α-KG content was measured in P7 cardiomyocytes treated with Ogdh siRNA (si-Ogdh) or without (Scramble) transfection (n = 5, n value refers to independent experiments). Molecular weight marker (kDa) is shown. Statistical analysis was evaluated using One-way ANOVA with the Dunnett’s multiple comparisons test in b-d; Two-tailed, unpaired Student t-tests in e and f. Values are mean ± SEM. For heat maps, the color-shift from blue to red indicates increasing levels of corresponding metabolites. Uncropped blots for c are provided in Supplementary Source Data.
Extended Data Fig. 9 Administration of AAV9-sh-Ogdh in MI model.
a, Schematic diagram of AAV9-sh-Ogdh construct. b, Schematic diagram of the intravenous delivery of AAV9-Ogdh. c, Representative immunofluorescence images of cTnT and GFP staining in the heart samples from mice injected with AAV9-Gfp or AAV9-sh-Ogdh at 2 weeks post-MI (n = 3 hearts per group, Scale bar = 50 μm). d, Western blots show the expression of OGDH in dissociated cardiomyocytes of AAV9-sh-Ogdh and AAV9-Gfp mice at indicated timepoints (n = 6 hearts per group). e, Quantification of Ogdh activity in adult cardiomyocytes isolated from AAV9-Gfp and AAV9-sh-Ogdh mice at 2 weeks post-MI (n = 4 hearts per group). f, Relative abundance of α-KG in dissociated cardiomyocytes showing a significant increase in α-KG levels in AAV9-sh-Ogdh mice at 14 days post-MI (n = 5 hearts per group, *P < 0.05). g, JMJD3 activity of adult cardiomyocytes dissociated from AAV9-sh-Ogdh and AAV9-Gfp mice at day 14 post-MI (n = 5 hearts per group, *P < 0.05). h, H3K27me3 level protein in adult cardiomyocytes dissociated from AAV9-sh-Ogdh and AAV9-Gfp mice at day 14 post-MI (n = 6 hearts per group, *P < 0.05). i, Representative images and quantification of TUNEL-positive cardiomyocytes in AAV9-sh-Ogdh and AAV9-Gfp mice at day 14 post-MI (white arrows point to Tune+/cTnT+ CMs, amplified area outlined in main image indicates typically stained CMs, Scale bar = 50 μm, n = 6 hearts per group, *P < 0.05). j, Quantification of cardiomyocyte size by wheat germ agglutinin (WGA) staining in AAV9-sh-Ogdh and AAV9-Gfp hearts at 28 days post-MI (More than 200 cardiomyocytes per group, Top right of the main image: amplified area outlined in main image, Scale bar = 50 μm, n = 5, *P < 0.05). Molecular weight marker (kDa) is shown. Statistical analysis was evaluated using Two-tailed, unpaired Student t-tests in d-I; Two-way ANOVA with the Sidak’s multiple comparisons test in j. AAV9-Gfp was used as control. Values are mean ± SEM. Uncropped blots for d and h are provided in Supplementary Source Data.
Supplementary information
Supplementary Information
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Supplementary Video 1
Images of proliferating ACMs with completed cytokinesis are captured by live cell imaging, using time-lapse microscopy. Green fluorescence depicts ACMs isolated from adult GFP transgenic mouse. Proliferation (with completed cytokinesis) of a binucleated ACM isolated from transgenic GFP mouse cocultured with NRVMs was recorded by live cell imaging, using time-lapse microscopy. ACMs were treated with α-KG (5 mM) or vehicle. PBS was used as the control. Representative frames of this video at different time points are shown in Fig. 3b.
Supplementary Video 2
Images of proliferating ACMs with completed cytokinesis are captured by live cell imaging, using time-lapse microscopy. Green fluorescence depicts ACMs isolated from adult GFP transgenic mouse. Proliferation (with completed cytokinesis) of a binucleated ACM isolated from transgenic GFP mouse cocultured with NRVMs was recorded by live cell imaging, using time-lapse microscopy. ACMs were treated with α-KG (5 mM) or vehicle. PBS was used as the control. Representative frames of this video at different time points are shown in Fig. 3b.
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Shi, Y., Tian, M., Zhao, X. et al. α-Ketoglutarate promotes cardiomyocyte proliferation and heart regeneration after myocardial infarction. Nat Cardiovasc Res 3, 1083–1097 (2024). https://doi.org/10.1038/s44161-024-00531-y
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DOI: https://doi.org/10.1038/s44161-024-00531-y
