Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal Sheep
Fetuses with intrauterine growth restriction (FGR) have impaired oxidative and energy metabolism, with persistent consequences on their postnatal development. In this study, we test the hypothesis that FGR skeletal muscle has lower mitochondrial respiration rate and alters the transcriptomic profile...
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/21/15760 |
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| author | Weicheng Zhao Amy C. Kelly Rosa I. Luna-Ramirez Christopher A. Bidwell Miranda J. Anderson Sean W. Limesand |
| author_facet | Weicheng Zhao Amy C. Kelly Rosa I. Luna-Ramirez Christopher A. Bidwell Miranda J. Anderson Sean W. Limesand |
| author_sort | Weicheng Zhao |
| collection | DOAJ |
| description | Fetuses with intrauterine growth restriction (FGR) have impaired oxidative and energy metabolism, with persistent consequences on their postnatal development. In this study, we test the hypothesis that FGR skeletal muscle has lower mitochondrial respiration rate and alters the transcriptomic profiles associated with energy metabolism in an ovine model. At late gestation, mitochondrial oxygen consumption rates (OCRs) and transcriptome profiles were evaluated in the skeletal muscle collected from FGR and control fetuses. The ex vivo mitochondrial OCRs were reduced <i>(p</i> < 0.01) in permeabilized FGR soleus muscle compared to the control muscle but only with pyruvate as the metabolic substrate. Mitochondrial OCRs were similar between the FGR and control groups for palmitoyl-carnitine (fatty acid-driven) or pyruvate plus palmitoyl-carnitine metabolic substrates. A total of 2284 genes were differentially expressed in the semitendinosus muscle from growth restricted fetuses (false discovery rate (FDR) ≤ 0.05). A pathway analysis showed that the upregulated genes (FGR compared to control) were overrepresented for autophagy, HIF-1, AMPK, and FOXO signaling pathways (all with an FDR < 0.05). In addition, the expression of genes modulating pyruvate’s entry into the TCA cycle was downregulated, whereas the genes encoding key fatty acid oxidation enzymes were upregulated in the FGR muscle. These findings show that FGR skeletal muscle had attenuated mitochondrial pyruvate oxidation, possibly associated with the inability of pyruvate to enter into the TCA cycle, and that fatty acid oxidation might compensate for the attenuated energy metabolism. The current study provided phenotypic and molecular evidence for adaptive deficiencies in FGR skeletal muscle. |
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| language | English |
| last_indexed | 2024-03-11T11:27:59Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-04a3d309bc7e420680bec22e52a2aed72023-11-10T15:05:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124211576010.3390/ijms242115760Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal SheepWeicheng Zhao0Amy C. Kelly1Rosa I. Luna-Ramirez2Christopher A. Bidwell3Miranda J. Anderson4Sean W. Limesand5School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85719, USASchool of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85719, USASchool of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85719, USADepartment of Animal Sciences, Purdue University, West Lafayette, IN 47907, USASchool of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85719, USASchool of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85719, USAFetuses with intrauterine growth restriction (FGR) have impaired oxidative and energy metabolism, with persistent consequences on their postnatal development. In this study, we test the hypothesis that FGR skeletal muscle has lower mitochondrial respiration rate and alters the transcriptomic profiles associated with energy metabolism in an ovine model. At late gestation, mitochondrial oxygen consumption rates (OCRs) and transcriptome profiles were evaluated in the skeletal muscle collected from FGR and control fetuses. The ex vivo mitochondrial OCRs were reduced <i>(p</i> < 0.01) in permeabilized FGR soleus muscle compared to the control muscle but only with pyruvate as the metabolic substrate. Mitochondrial OCRs were similar between the FGR and control groups for palmitoyl-carnitine (fatty acid-driven) or pyruvate plus palmitoyl-carnitine metabolic substrates. A total of 2284 genes were differentially expressed in the semitendinosus muscle from growth restricted fetuses (false discovery rate (FDR) ≤ 0.05). A pathway analysis showed that the upregulated genes (FGR compared to control) were overrepresented for autophagy, HIF-1, AMPK, and FOXO signaling pathways (all with an FDR < 0.05). In addition, the expression of genes modulating pyruvate’s entry into the TCA cycle was downregulated, whereas the genes encoding key fatty acid oxidation enzymes were upregulated in the FGR muscle. These findings show that FGR skeletal muscle had attenuated mitochondrial pyruvate oxidation, possibly associated with the inability of pyruvate to enter into the TCA cycle, and that fatty acid oxidation might compensate for the attenuated energy metabolism. The current study provided phenotypic and molecular evidence for adaptive deficiencies in FGR skeletal muscle.https://www.mdpi.com/1422-0067/24/21/15760intrauterine growth restrictionmitochondriaskeletal musclefetusdevelopmental programming |
| spellingShingle | Weicheng Zhao Amy C. Kelly Rosa I. Luna-Ramirez Christopher A. Bidwell Miranda J. Anderson Sean W. Limesand Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal Sheep International Journal of Molecular Sciences intrauterine growth restriction mitochondria skeletal muscle fetus developmental programming |
| title | Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal Sheep |
| title_full | Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal Sheep |
| title_fullStr | Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal Sheep |
| title_full_unstemmed | Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal Sheep |
| title_short | Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal Sheep |
| title_sort | decreased pyruvate but not fatty acid driven mitochondrial respiration in skeletal muscle of growth restricted fetal sheep |
| topic | intrauterine growth restriction mitochondria skeletal muscle fetus developmental programming |
| url | https://www.mdpi.com/1422-0067/24/21/15760 |
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