GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc
Glycolysis is central to homeostasis of nucleus pulposus (NP) cells in the avascular intervertebral disc. Since the glucose transporter, GLUT1, is a highly enriched phenotypic marker of NP cells, we hypothesized that it is vital for the development and postnatal maintenance of the disc. Surprisingly...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-04-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.164883 |
| _version_ | 1797634304908460032 |
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| author | Shira N. Johnston Elizabeth S. Silagi Vedavathi Madhu Duc H. Nguyen Irving M. Shapiro Makarand V. Risbud |
| author_facet | Shira N. Johnston Elizabeth S. Silagi Vedavathi Madhu Duc H. Nguyen Irving M. Shapiro Makarand V. Risbud |
| author_sort | Shira N. Johnston |
| collection | DOAJ |
| description | Glycolysis is central to homeostasis of nucleus pulposus (NP) cells in the avascular intervertebral disc. Since the glucose transporter, GLUT1, is a highly enriched phenotypic marker of NP cells, we hypothesized that it is vital for the development and postnatal maintenance of the disc. Surprisingly, primary NP cells treated with 2 well-characterized GLUT1 inhibitors maintained normal rates of glycolysis and ATP production, indicating intrinsic compensatory mechanisms. We showed in vitro that NP cells mitigated GLUT1 loss by rewiring glucose import through GLUT3. Of note, we demonstrated that substrates, such as glutamine and palmitate, did not compensate for glucose restriction resulting from dual inhibition of GLUT1/3, and inhibition compromised long-term cell viability. To investigate the redundancy of GLUT1 function in NP, we generated 2 NP-specific knockout mice: Krt19CreERT Glut1fl/fl and Foxa2Cre Glut1fl/fl. There were no apparent defects in postnatal disc health or development and maturation in mutant mice. Microarray analysis verified that GLUT1 loss did not cause transcriptomic alterations in the NP, supporting that cells are refractory to GLUT1 loss. These observations provide the first evidence to our knowledge of functional redundancy in GLUT transporters in the physiologically hypoxic intervertebral disc and underscore the importance of glucose as the indispensable substrate for NP cells. |
| first_indexed | 2024-03-11T12:06:44Z |
| format | Article |
| id | doaj.art-7f6d072756be4811ab2328a2c665c617 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:44Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-7f6d072756be4811ab2328a2c665c6172023-11-07T16:25:31ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-04-0188GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral discShira N. JohnstonElizabeth S. SilagiVedavathi MadhuDuc H. NguyenIrving M. ShapiroMakarand V. RisbudGlycolysis is central to homeostasis of nucleus pulposus (NP) cells in the avascular intervertebral disc. Since the glucose transporter, GLUT1, is a highly enriched phenotypic marker of NP cells, we hypothesized that it is vital for the development and postnatal maintenance of the disc. Surprisingly, primary NP cells treated with 2 well-characterized GLUT1 inhibitors maintained normal rates of glycolysis and ATP production, indicating intrinsic compensatory mechanisms. We showed in vitro that NP cells mitigated GLUT1 loss by rewiring glucose import through GLUT3. Of note, we demonstrated that substrates, such as glutamine and palmitate, did not compensate for glucose restriction resulting from dual inhibition of GLUT1/3, and inhibition compromised long-term cell viability. To investigate the redundancy of GLUT1 function in NP, we generated 2 NP-specific knockout mice: Krt19CreERT Glut1fl/fl and Foxa2Cre Glut1fl/fl. There were no apparent defects in postnatal disc health or development and maturation in mutant mice. Microarray analysis verified that GLUT1 loss did not cause transcriptomic alterations in the NP, supporting that cells are refractory to GLUT1 loss. These observations provide the first evidence to our knowledge of functional redundancy in GLUT transporters in the physiologically hypoxic intervertebral disc and underscore the importance of glucose as the indispensable substrate for NP cells.https://doi.org/10.1172/jci.insight.164883Bone biologyMetabolism |
| spellingShingle | Shira N. Johnston Elizabeth S. Silagi Vedavathi Madhu Duc H. Nguyen Irving M. Shapiro Makarand V. Risbud GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc JCI Insight Bone biology Metabolism |
| title | GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc |
| title_full | GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc |
| title_fullStr | GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc |
| title_full_unstemmed | GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc |
| title_short | GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc |
| title_sort | glut1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc |
| topic | Bone biology Metabolism |
| url | https://doi.org/10.1172/jci.insight.164883 |
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