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The Na/K-ATPase α1/Src interaction regulates metabolic reserve and Western diet intolerance.

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Title: The Na/K-ATPase α1/Src interaction regulates metabolic reserve and Western diet intolerance.
Authors: Kutz, Laura C., Xiaoyu Cui, Xie, Jeffrey X., Mukherji, Shreya T., Terrell, Kayleigh C., Minqi Huang, Xiaoliang Wang, Jiayan Wang, Martin, Adam J., Pessoa, Marco T., Liquan Cai, Hua Zhu, Heiny, Judith A., Shapiro, Joseph I., Blanco, Gustavo, Zijian Xie, Pierre, Sandrine V.
Source: Acta Physiologica. Jul2021, Vol. 232 Issue 3, p1-19. 19p.
Subjects: Western diet, Metabolic flux analysis, Glucose intolerance, Metabolic disorders, Glucose analysis
Abstract: Aim: Highly prevalent diseases such as insulin resistance and heart failure are characterized by reduced metabolic flexibility and reserve. We tested whether Na/K-ATPase (NKA)-mediated regulation of Src kinase, which requires two NKA sequences specific to the α1 isoform, is a regulator of metabolic capacity that can be targeted pharmacologically. Methods: Metabolic capacity was challenged functionally by Seahorse metabolic flux analyses and glucose deprivation in LLC-PK1-derived cells expressing Src binding rat NKA α1, non-Src-binding rat NKA α2 (the most abundant NKA isoform in the skeletal muscle), and Src binding gain-of-function mutant rat NKA α2. Mice with skeletal muscle-specific ablation of NKA α1 (skα1-/-) were generated using a MyoD:Cre-Lox approach and were subjected to treadmill testing and Western diet. C57/Bl6 mice were subjected to Western diet with or without pharmacological inhibition of NKA α1/Src modulation by treatment with pNaKtide, a cell-permeable peptide designed by mapping one of the sites of NKA α1/Src interaction. Results: Metabolic studies in mutant cell lines revealed that the Src binding regions of NKA α1 are required to maintain metabolic reserve and flexibility. Skα1-/-mice had decreased exercise endurance and mitochondrial Complex I dysfunction. However, skα1-/-mice were resistant to Western diet-induced insulin resistance and glucose intolerance, a protection phenocopied by pharmacological inhibition of NKA α1-mediated Src regulation with pNaKtide. Conclusions: These results suggest that NKA α1/Src regulatory function may be targeted in metabolic diseases. Because Src regulatory capability by NKA α1 is exclusive to endotherms, it may link the aerobic scope hypothesis of endothermy evolution to metabolic dysfunction. [ABSTRACT FROM AUTHOR]
Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: The Na/K-ATPase α1/Src interaction regulates metabolic reserve and Western diet intolerance.
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  Data: <searchLink fieldCode="AR" term="%22Kutz%2C+Laura+C%2E%22">Kutz, Laura C.</searchLink><br /><searchLink fieldCode="AR" term="%22Xiaoyu+Cui%22">Xiaoyu Cui</searchLink><br /><searchLink fieldCode="AR" term="%22Xie%2C+Jeffrey+X%2E%22">Xie, Jeffrey X.</searchLink><br /><searchLink fieldCode="AR" term="%22Mukherji%2C+Shreya+T%2E%22">Mukherji, Shreya T.</searchLink><br /><searchLink fieldCode="AR" term="%22Terrell%2C+Kayleigh+C%2E%22">Terrell, Kayleigh C.</searchLink><br /><searchLink fieldCode="AR" term="%22Minqi+Huang%22">Minqi Huang</searchLink><br /><searchLink fieldCode="AR" term="%22Xiaoliang+Wang%22">Xiaoliang Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Jiayan+Wang%22">Jiayan Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Martin%2C+Adam+J%2E%22">Martin, Adam J.</searchLink><br /><searchLink fieldCode="AR" term="%22Pessoa%2C+Marco+T%2E%22">Pessoa, Marco T.</searchLink><br /><searchLink fieldCode="AR" term="%22Liquan+Cai%22">Liquan Cai</searchLink><br /><searchLink fieldCode="AR" term="%22Hua+Zhu%22">Hua Zhu</searchLink><br /><searchLink fieldCode="AR" term="%22Heiny%2C+Judith+A%2E%22">Heiny, Judith A.</searchLink><br /><searchLink fieldCode="AR" term="%22Shapiro%2C+Joseph+I%2E%22">Shapiro, Joseph I.</searchLink><br /><searchLink fieldCode="AR" term="%22Blanco%2C+Gustavo%22">Blanco, Gustavo</searchLink><br /><searchLink fieldCode="AR" term="%22Zijian+Xie%22">Zijian Xie</searchLink><br /><searchLink fieldCode="AR" term="%22Pierre%2C+Sandrine+V%2E%22">Pierre, Sandrine V.</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Acta+Physiologica%22">Acta Physiologica</searchLink>. Jul2021, Vol. 232 Issue 3, p1-19. 19p.
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  Data: <searchLink fieldCode="DE" term="%22Western+diet%22">Western diet</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolic+flux+analysis%22">Metabolic flux analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Glucose+intolerance%22">Glucose intolerance</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolic+disorders%22">Metabolic disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Glucose+analysis%22">Glucose analysis</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Aim: Highly prevalent diseases such as insulin resistance and heart failure are characterized by reduced metabolic flexibility and reserve. We tested whether Na/K-ATPase (NKA)-mediated regulation of Src kinase, which requires two NKA sequences specific to the α1 isoform, is a regulator of metabolic capacity that can be targeted pharmacologically. Methods: Metabolic capacity was challenged functionally by Seahorse metabolic flux analyses and glucose deprivation in LLC-PK1-derived cells expressing Src binding rat NKA α1, non-Src-binding rat NKA α2 (the most abundant NKA isoform in the skeletal muscle), and Src binding gain-of-function mutant rat NKA α2. Mice with skeletal muscle-specific ablation of NKA α1 (skα1-/-) were generated using a MyoD:Cre-Lox approach and were subjected to treadmill testing and Western diet. C57/Bl6 mice were subjected to Western diet with or without pharmacological inhibition of NKA α1/Src modulation by treatment with pNaKtide, a cell-permeable peptide designed by mapping one of the sites of NKA α1/Src interaction. Results: Metabolic studies in mutant cell lines revealed that the Src binding regions of NKA α1 are required to maintain metabolic reserve and flexibility. Skα1-/-mice had decreased exercise endurance and mitochondrial Complex I dysfunction. However, skα1-/-mice were resistant to Western diet-induced insulin resistance and glucose intolerance, a protection phenocopied by pharmacological inhibition of NKA α1-mediated Src regulation with pNaKtide. Conclusions: These results suggest that NKA α1/Src regulatory function may be targeted in metabolic diseases. Because Src regulatory capability by NKA α1 is exclusive to endotherms, it may link the aerobic scope hypothesis of endothermy evolution to metabolic dysfunction. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1111/apha.13652
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        Text: English
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      – SubjectFull: Western diet
        Type: general
      – SubjectFull: Metabolic flux analysis
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      – SubjectFull: Glucose intolerance
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