Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts
Abstract Metabolic plasticity in a hostile environment ensures cell survival. We investigated whether Hippo pathway inhibition contributed to cell adaptations under challenging conditions. We examined metabolic profiles and fuel substrate choices and preferences in C2C12 myoblasts after Hippo pathwa...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-29372-8 |
| _version_ | 1811165920241909760 |
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| author | Qi Liu Su Pan Pengyang Li Richard A. F. Dixon |
| author_facet | Qi Liu Su Pan Pengyang Li Richard A. F. Dixon |
| author_sort | Qi Liu |
| collection | DOAJ |
| description | Abstract Metabolic plasticity in a hostile environment ensures cell survival. We investigated whether Hippo pathway inhibition contributed to cell adaptations under challenging conditions. We examined metabolic profiles and fuel substrate choices and preferences in C2C12 myoblasts after Hippo pathway inhibition via Salvador knockdown (SAV1 KD). SAV1 KD induced higher ATP production and a more energetic phenotype. Bioenergetic profiling showed enhanced key mitochondrial parameters including spare respiratory capacity. SAV1 KD cells showed markedly elevated glycolysis and glycolytic reserves; blocking other fuel-oxidation pathways enhanced mitochondrial flexibility of glucose oxidation. Under limited glucose, endogenous fatty acid oxidation increased to cope with bioenergetic stress. Gene expression patterns after SAV1 KD suggested transcriptional upregulation of key metabolic network regulators to promote energy production and free radical scavenging that may prevent impaired lipid and glucose metabolism. In SAV1 KD cells, sirtuin signaling was the top enriched canonical pathway linked with enhanced mitochondrial ATP production. Collectively, we demonstrated that Hippo pathway inhibition in SAV1 KD cells induces multiple metabolic properties, including enhancing mitochondrial spare respiratory capacity or glycolytic reserve to cope with stress and upregulating metabolic pathways supporting elevated ATP demand, bioenergetics, and glycolysis and counteracting oxidative stress. In response to metabolic challenges, SAV1 KD cells can increase fatty acid oxidation or glucose-coupled oxidative phosphorylation capacity to compensate for substrate limitations or alternative fuel oxidation pathway inhibition. |
| first_indexed | 2024-04-10T15:45:08Z |
| format | Article |
| id | doaj.art-41d9c3916c59437ba5281f9debac7f81 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-10T15:45:08Z |
| publishDate | 2023-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-41d9c3916c59437ba5281f9debac7f812023-02-12T12:10:21ZengNature PortfolioScientific Reports2045-23222023-02-0113111410.1038/s41598-023-29372-8Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblastsQi Liu0Su Pan1Pengyang Li2Richard A. F. Dixon3Wafic Said Molecular Cardiology Research Laboratories, The Texas Heart InstituteWafic Said Molecular Cardiology Research Laboratories, The Texas Heart InstituteDivision of Cardiology, Pauley Heart Center, Virginia Commonwealth UniversityWafic Said Molecular Cardiology Research Laboratories, The Texas Heart InstituteAbstract Metabolic plasticity in a hostile environment ensures cell survival. We investigated whether Hippo pathway inhibition contributed to cell adaptations under challenging conditions. We examined metabolic profiles and fuel substrate choices and preferences in C2C12 myoblasts after Hippo pathway inhibition via Salvador knockdown (SAV1 KD). SAV1 KD induced higher ATP production and a more energetic phenotype. Bioenergetic profiling showed enhanced key mitochondrial parameters including spare respiratory capacity. SAV1 KD cells showed markedly elevated glycolysis and glycolytic reserves; blocking other fuel-oxidation pathways enhanced mitochondrial flexibility of glucose oxidation. Under limited glucose, endogenous fatty acid oxidation increased to cope with bioenergetic stress. Gene expression patterns after SAV1 KD suggested transcriptional upregulation of key metabolic network regulators to promote energy production and free radical scavenging that may prevent impaired lipid and glucose metabolism. In SAV1 KD cells, sirtuin signaling was the top enriched canonical pathway linked with enhanced mitochondrial ATP production. Collectively, we demonstrated that Hippo pathway inhibition in SAV1 KD cells induces multiple metabolic properties, including enhancing mitochondrial spare respiratory capacity or glycolytic reserve to cope with stress and upregulating metabolic pathways supporting elevated ATP demand, bioenergetics, and glycolysis and counteracting oxidative stress. In response to metabolic challenges, SAV1 KD cells can increase fatty acid oxidation or glucose-coupled oxidative phosphorylation capacity to compensate for substrate limitations or alternative fuel oxidation pathway inhibition.https://doi.org/10.1038/s41598-023-29372-8 |
| spellingShingle | Qi Liu Su Pan Pengyang Li Richard A. F. Dixon Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts Scientific Reports |
| title | Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts |
| title_full | Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts |
| title_fullStr | Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts |
| title_full_unstemmed | Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts |
| title_short | Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts |
| title_sort | hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts |
| url | https://doi.org/10.1038/s41598-023-29372-8 |
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