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Can Targeting Cardiomyocyte Metabolism Improve Cardiac Regeneration?

Review of “Mitochondrial substrate utilization regulates cardiomyocyte cell-cycle progression” from Nature Metabolism by Stuart P. Atkinson

The neonatal mammalian heart displays robust regenerative potential in the period just after birth; however, a metabolic shift from anaerobic glycolysis to mitochondrial oxidative phosphorylation during development,  particularly towards fatty-acid use [1, 2], coincides with the loss of this ability. Fatty acid metabolism causes the cardiac mitochondria to produce elevated rates of reactive oxygen species (ROS) [3-5], and researchers led by Alisson C. Cardoso and Hesham A. Sadek (University of Texas Southwestern Medical Center, Dallas, TX, USA) recently established that these ROS can induce a DNA damage response in the early postnatal heart, thereby prompting the cell cycle arrest of cardiomyocytes [6]. Given these findings, the team next sought to discover whether inhibiting fatty-acid utilization could reduce the ROS-mediated DNA damage response and promote cardiomyocyte proliferation in the postnatal heart [7].

The authors first studied the effect of feeding neonatal mice a fatty acid-free diet through mothers engineered not to produce fatty acids in milk and then supplying pups with fat-free food after weaning. Analysis of mouse pup hearts found that the absence of fatty acids in the diet prompted a modest prolongation of the postnatal proliferative window of cardiomyocytes before cell-cycle arrest at the ten-week stage, a timepoint that coincides with enhanced fatty acid synthesis by the liver.

Next, the authors engineered an inducible cardiomyocyte-specific pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse model that leads to increased pyruvate dehydrogenase activity and an increase in the oxidation of glucose at the expense of fatty acids. Fascinatingly, this metabolic switch resulted in a decrease in cardiomyocyte size, DNA damage levels (both base oxidation and double-strand breaks), and DNA damage response marker expression and an increase in cardiomyocyte proliferation in the adult mouse. Encouragingly, the induced knockout of PDK4 after experimental myocardial infarction also prompted an improvement in left ventricular function and decreased cardiac remodeling. At the same time, the authors also found proof that the pharmacological inhibition of PDK4 in adult mice could also promote cardiomyocyte proliferation.

Overall, this study provides evidence that fatty-acid utilization significantly contributes to postnatal cardiomyocyte cell-cycle arrest through DNA damage-associated pathways, and that small molecule-based targeting of PDK4 may represent an efficient means to induce cardiomyocyte proliferation and prevent myocardial remodeling in the adult heart.

For more on how targeting cardiomyocyte metabolism may impact cardiac regeneration, stay tuned to the Stem Cells Portal!

References

  1. Lopaschuk GD, Collins-Nakai RL, and Itoi T, Developmental Changes in Energy Substrate Use by the Heart. Cardiovascular Research 1992;26:1172-1180.
  2. Lehman JJ and Kelly DP, Transcriptional Activation of Energy Metabolic Switches in the Developing and Hypertrophied Heart. Clinical and Experimental Pharmacology and Physiology 2002;29:339-345.
  3. Anderson EJ, Yamazaki H, and Neufer PD, Induction of Endogenous Uncoupling Protein 3 Suppresses Mitochondrial Oxidant Emission during Fatty Acid-supported Respiration. Journal of Biological Chemistry 2007;282:31257-31266.
  4. Rindler PM, Plafker SM, Szweda LI, et al., High Dietary Fat Selectively Increases Catalase Expression within Cardiac Mitochondria. Journal of Biological Chemistry 2013;288:1979-1990.
  5. Seifert EL, Estey C, Xuan JY, et al., Electron Transport Chain-dependent and -independent Mechanisms of Mitochondrial H2O2 Emission during Long-chain Fatty Acid Oxidation. Journal of Biological Chemistry 2010;285:5748-5758.
  6. Puente Bao N, Kimura W, Muralidhar Shalini A, et al., The Oxygen-Rich Postnatal Environment Induces Cardiomyocyte Cell-Cycle Arrest through DNA Damage Response. Cell 2014;157:565-579.
  7. Cardoso AC, Lam NT, Savla JJ, et al., Mitochondrial Substrate Utilization Regulates Cardiomyocyte Cell-cycle Progression. Nature Metabolism 2020;2:167-178.