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Updated: May 12, 2025
Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration
Published on: May 24, 2016
Fatty acid metabolism suppresses neonatal cardiomyocyte proliferation by increasing PDK4 and HMGCS2 expression
Shota Tanaka1, Akane Hirota1, Yoshiaki Okada1
1Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Abstract:
Cardiomyocytes lose their capacity to regenerate immediately after birth. Simultaneously, cardiomyocytes change energy metabolism from glycolysis to oxidative phosphorylation, especially using fatty acids. Accumulating evidence has revealed that fatty acid metabolism weakens the proliferative ability of cardiomyocytes. However, its underlying molecular mechanism remains unclear. In this study, we investigated how fatty acid metabolism contributes to cell cycle regulation in neonatal cardiomyocytes. Cultured neonatal rat cardiomyocytes (NRCMs) were treated with a fatty acid mixture (FA) consisting of palmitic and oleic acids containing L-carnitine. The FA treatment increased not only β-oxidation-related enzymes but also pyruvate dehydrogenase kinase 4 (PDK4), a fatty acid metabolism regulator, and HMG-CoA synthase 2 (HMGCS2), a ketogenic factor. Moreover, Ki67-positive proliferative NRCMs were reduced by the FA, indicating that fatty acids suppress the NRCM cell cycle. GW501516, a peroxisome proliferator-activated receptor δ (PPARδ) activator, also upregulated fatty acid metabolism genes and disturbed NRCM proliferation, whereas GSK3787, a PPARδ inhibitor, recovered FA-induced the cell cycle arrest. Furthermore, overexpression of PDK4 or HMGCS2 using a lentiviral vector suppressed cell cycle activity in NRCMs, and silencing either gene regained cell cycle even in FA-rich condition. In conclusion, fatty acid metabolism increased PDK4 and HMGCS2 via PPARδ activation and suppressed NRCM proliferation.
Insights
Fatty acid metabolism, regulated by pyruvate dehydrogenase kinase 4 (PDK4) and HMG-CoA synthase 2 (HMGCS2) via PPARδ, suppresses neonatal cardiomyocyte proliferation and cell cycle activity.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Cardiomyocytes lose regenerative capacity post-birth, shifting metabolism to fatty acid oxidation.
- Fatty acid metabolism is implicated in suppressing cardiomyocyte proliferation, but mechanisms are unclear.
Purpose of the Study:
- To investigate the molecular mechanisms by which fatty acid metabolism regulates cell cycle in neonatal cardiomyocytes.
- To elucidate the role of PDK4 and HMGCS2 in fatty acid-induced suppression of cardiomyocyte proliferation.
Main Methods:
- Neonatal rat cardiomyocytes (NRCMs) were cultured and treated with fatty acids (FA), PPARδ activator (GW501516), or PPARδ inhibitor (GSK3787).
- Gene expression of β-oxidation enzymes, PDK4, and HMGCS2 was analyzed.
- Cell proliferation was assessed by Ki67 staining.
- Overexpression and silencing of PDK4 and HMGCS2 were performed using lentiviral vectors.
Main Results:
- FA treatment increased β-oxidation enzymes, PDK4, and HMGCS2, while reducing Ki67-positive NRCMs.
- PPARδ activation upregulated fatty acid metabolism and inhibited NRCM proliferation; PPARδ inhibition reversed these effects.
- Overexpression of PDK4 or HMGCS2 suppressed NRCM cell cycle activity.
- Silencing PDK4 or HMGCS2 restored cell cycle progression even under FA-rich conditions.
Conclusions:
- Fatty acid metabolism, mediated by PPARδ activation, increases PDK4 and HMGCS2 expression.
- Elevated PDK4 and HMGCS2 suppress neonatal cardiomyocyte proliferation by inhibiting cell cycle activity.
- Targeting fatty acid metabolism pathways may offer strategies to enhance cardiac regeneration.
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