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Fatty acid oxidation restriction triggered by Cpt1b deficiency specific in adult cardiomyocyte (CM) with aMHC-MCM promotes CM dedifferentiation [RNA-seq II]

ABSTRACT: In the heart, metabolic profile switches from glycolysis to fatty acid oxidation (FAO) rapidly after birth accompanied by chromatin reconfiguration, cell cycle exit and cardiomyocyte (CM) maturation, suggesting a synergistic rewiring of transcriptional networks regulated by epigenetic mechanisms in accordance with environmental and metabolic signals. To gain a better insight into the interconnection between epigenetic processes and metabolic pathways during cardiac development, maturation and heart regeneration, we induced a metabolic reprogramming by depleting CPT1b, a crucial enzyme for FAO, specifically in CM. Cpt1b inactivation led to cardiomegaly and attenuated cardiac damage in response to myocardial injury primarily attributed to augmented CM proliferation and enhanced resistance to ischemic injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE172414 | GEO | 2023/07/18

REPOSITORIES: GEO

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Project description:CPT1B, as the major rate-limiting enzyme for fatty acid β-oxidation, involved in the regulation of adipose tissue lipid deposition, but its role in the regulation of goat intramuscular fat (IMF) remains unclear. Here, we conducted knockdown experiments targeting the CPT1B gene in goat intramuscular preadipocytes, resulting in a significant increase in intracellular triglyceride (TAG) content and lipid droplet accumulation. Conversely, the overexpression of CPT1B led to a significant decrease in intracellular TAG content and lipid droplet accumulation. Mechanistically, through RNA-seq analysis of CPT1B knockdown samples, we identified 285 differentially expressed genes (DEGs), including 71 up-regulated and 214 down-regulated genes. Notably, these DEGs were significantly enriched in various KEGG signaling pathways, such as fatty acid metabolism, focal adhesion, FoxO signaling, PI3K-Akt signaling, and MAPK signaling pathways. Gene Set Enrichment Analysis (GSEA) further confirmed the upregulation of the MAPK signaling pathway upon CPT1B knockdown in adipocytes. In rescue experiments, we demonstrated that the addition of a p38MAPK inhibitor (PD169316) to CPT1B-knockdown adipocytes counteracted the increase in lipid deposition caused by the loss of CPT1B function. These findings suggest that CPT1B inhibits lipid deposition in goat intramuscular preadipocytes via the p38MAPK signaling pathway. In addition, we observed a potential interaction between CPT1B and CPT1A through Protein-Protein Interaction Networks (PPIs). Interestingly, CPT1A exhibited a similar regulatory function to CPT1B, and they both were able to partially restore the changes in lipid deposition induced by each other. This observation supports the hypothesis of synergistic effects between CPT1B and CPT1A. Collectively, our results elucidate the role of CPT1B in the regulation of lipid deposition in goat intramuscular adipocytes through the p38MAPK signaling pathway, providing valuable insights for enhancing the quality of goat intramuscular fat.

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Fatty acid oxidation restriction triggered by Cpt1b deficiency specific in adult cardiomyocyte (CM) with aMHC-MCM promotes CM dedifferentiation [RNA-seq II]

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