Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart

Golam M. Uddin; Qutuba G. Karwi; Simran Pherwani; Keshav Gopal; Cory S. Wagg; Dipsikha Biswas; Mariam Atnasious; Yikuan Wu; Guoqing Wu; Liyan Zhang; Kim L. Ho; Thomas Pulinilkunnil; John R. Ussher; Gary D. Lopaschuk

doi:10.1016/j.metabol.2021.154871

Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart

Golam M. Uddin, Qutuba G. Karwi, Simran Pherwani, Keshav Gopal, Cory S. Wagg, Dipsikha Biswas, Mariam Atnasious, Yikuan Wu, Guoqing Wu, Liyan Zhang, Kim L. Ho, Thomas Pulinilkunnil, John R. Ussher, Gary D. Lopaschuk

Medicine

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29 Citas (Scopus)

Resumen

Backgrounds: Branched chain amino acid (BCAA) oxidation is impaired in cardiac insulin resistance, leading to the accumulation of BCAAs and the first products of BCAA oxidation, the branched chain ketoacids. However, it is not clear whether it is the BCAAs, BCKAs or both that are mediating cardiac insulin resistance. To determine this, we produced mice with a cardiac-specific deletion of BCAA aminotransferase (BCATm^−/−), the first enzyme in the BCAA oxidation pathway that is responsible for converting BCAAs to BCKAs. Methods: Eight-week-old BCATm cardiac specific knockout (BCATm^−/−) male mice and their α-MHC (myosin heavy chain) - Cre expressing wild type littermates (WT-Cre^+/+) received tamoxifen (50 mg/kg i.p. 6 times over 8 days). At 16-weeks of age, cardiac energy metabolism was assessed in isolated working hearts. Results: BCATm^−/− mice have decreased cardiac BCAA oxidation rates, increased cardiac BCAAs and a reduction in cardiac BCKAs. Hearts from BCATm^−/− mice showed an increase in insulin stimulation of glucose oxidation and an increase in p-AKT. To determine the impact of reversing these events, we perfused isolated working mice hearts with high levels of BCKAs, which completely abolished insulin-stimulated glucose oxidation rates, an effect associated with decreased p-AKT and inactivation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme in glucose oxidation. Conclusion: This implicates the BCKAs, and not BCAAs, as the actual mediators of cardiac insulin resistance and suggests that lowering cardiac BCKAs can be used as a therapeutic strategy to improve insulin sensitivity in the heart.

Idioma original	English
Número de artículo	154871
Publicación	Metabolism: Clinical and Experimental
Volumen	124
DOI	https://doi.org/10.1016/j.metabol.2021.154871
Estado	Published - nov. 2021

Nota bibliográfica

Funding Information:
We thank Dr. Susan M. Hutson (Virginia Polytechnic Institute and State University) for kindly providing us with the BCATmflox mice line. All animal protocols were approved by the University of Alberta Institutional Animal Care and Use Committee, which conform with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (eighth edition; revised 2011) and the guidelines of the Canadian Council on Animal Care. This study was supported by a grant from the Heart and Stroke Foundation of Canada to GDL. All data are available in the Lopaschuk Laboratory. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Gary D. Lopaschuk (glopasch@ualberta.ca).

Funding Information:
This study was supported by a grant from the Heart and Stroke Foundation of Canada to GDL.

Publisher Copyright:
© 2021

ASJC Scopus Subject Areas

Endocrinology, Diabetes and Metabolism
Endocrinology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

ODS de las Naciones Unidas

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Uddin, G. M., Karwi, Q. G., Pherwani, S., Gopal, K., Wagg, C. S., Biswas, D., Atnasious, M., Wu, Y., Wu, G., Zhang, L., Ho, K. L., Pulinilkunnil, T., Ussher, J. R., & Lopaschuk, G. D. (2021). Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart. Metabolism: Clinical and Experimental, 124, Artículo 154871. https://doi.org/10.1016/j.metabol.2021.154871

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title = "Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart",

abstract = "Backgrounds: Branched chain amino acid (BCAA) oxidation is impaired in cardiac insulin resistance, leading to the accumulation of BCAAs and the first products of BCAA oxidation, the branched chain ketoacids. However, it is not clear whether it is the BCAAs, BCKAs or both that are mediating cardiac insulin resistance. To determine this, we produced mice with a cardiac-specific deletion of BCAA aminotransferase (BCATm−/−), the first enzyme in the BCAA oxidation pathway that is responsible for converting BCAAs to BCKAs. Methods: Eight-week-old BCATm cardiac specific knockout (BCATm−/−) male mice and their α-MHC (myosin heavy chain) - Cre expressing wild type littermates (WT-Cre+/+) received tamoxifen (50 mg/kg i.p. 6 times over 8 days). At 16-weeks of age, cardiac energy metabolism was assessed in isolated working hearts. Results: BCATm−/− mice have decreased cardiac BCAA oxidation rates, increased cardiac BCAAs and a reduction in cardiac BCKAs. Hearts from BCATm−/− mice showed an increase in insulin stimulation of glucose oxidation and an increase in p-AKT. To determine the impact of reversing these events, we perfused isolated working mice hearts with high levels of BCKAs, which completely abolished insulin-stimulated glucose oxidation rates, an effect associated with decreased p-AKT and inactivation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme in glucose oxidation. Conclusion: This implicates the BCKAs, and not BCAAs, as the actual mediators of cardiac insulin resistance and suggests that lowering cardiac BCKAs can be used as a therapeutic strategy to improve insulin sensitivity in the heart.",

author = "Uddin, {Golam M.} and Karwi, {Qutuba G.} and Simran Pherwani and Keshav Gopal and Wagg, {Cory S.} and Dipsikha Biswas and Mariam Atnasious and Yikuan Wu and Guoqing Wu and Liyan Zhang and Ho, {Kim L.} and Thomas Pulinilkunnil and Ussher, {John R.} and Lopaschuk, {Gary D.}",

note = "Funding Information: We thank Dr. Susan M. Hutson (Virginia Polytechnic Institute and State University) for kindly providing us with the BCATmflox mice line. All animal protocols were approved by the University of Alberta Institutional Animal Care and Use Committee, which conform with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (eighth edition; revised 2011) and the guidelines of the Canadian Council on Animal Care. This study was supported by a grant from the Heart and Stroke Foundation of Canada to GDL. All data are available in the Lopaschuk Laboratory. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Gary D. Lopaschuk (glopasch@ualberta.ca). Funding Information: This study was supported by a grant from the Heart and Stroke Foundation of Canada to GDL. Publisher Copyright: {\textcopyright} 2021",

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doi = "10.1016/j.metabol.2021.154871",

language = "English",

volume = "124",

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T1 - Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart

AU - Uddin, Golam M.

AU - Karwi, Qutuba G.

AU - Pherwani, Simran

AU - Gopal, Keshav

AU - Wagg, Cory S.

AU - Biswas, Dipsikha

AU - Atnasious, Mariam

AU - Wu, Yikuan

AU - Wu, Guoqing

AU - Zhang, Liyan

AU - Ho, Kim L.

AU - Pulinilkunnil, Thomas

AU - Ussher, John R.

AU - Lopaschuk, Gary D.

N1 - Funding Information: We thank Dr. Susan M. Hutson (Virginia Polytechnic Institute and State University) for kindly providing us with the BCATmflox mice line. All animal protocols were approved by the University of Alberta Institutional Animal Care and Use Committee, which conform with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (eighth edition; revised 2011) and the guidelines of the Canadian Council on Animal Care. This study was supported by a grant from the Heart and Stroke Foundation of Canada to GDL. All data are available in the Lopaschuk Laboratory. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Gary D. Lopaschuk (glopasch@ualberta.ca). Funding Information: This study was supported by a grant from the Heart and Stroke Foundation of Canada to GDL. Publisher Copyright: © 2021

PY - 2021/11

Y1 - 2021/11

N2 - Backgrounds: Branched chain amino acid (BCAA) oxidation is impaired in cardiac insulin resistance, leading to the accumulation of BCAAs and the first products of BCAA oxidation, the branched chain ketoacids. However, it is not clear whether it is the BCAAs, BCKAs or both that are mediating cardiac insulin resistance. To determine this, we produced mice with a cardiac-specific deletion of BCAA aminotransferase (BCATm−/−), the first enzyme in the BCAA oxidation pathway that is responsible for converting BCAAs to BCKAs. Methods: Eight-week-old BCATm cardiac specific knockout (BCATm−/−) male mice and their α-MHC (myosin heavy chain) - Cre expressing wild type littermates (WT-Cre+/+) received tamoxifen (50 mg/kg i.p. 6 times over 8 days). At 16-weeks of age, cardiac energy metabolism was assessed in isolated working hearts. Results: BCATm−/− mice have decreased cardiac BCAA oxidation rates, increased cardiac BCAAs and a reduction in cardiac BCKAs. Hearts from BCATm−/− mice showed an increase in insulin stimulation of glucose oxidation and an increase in p-AKT. To determine the impact of reversing these events, we perfused isolated working mice hearts with high levels of BCKAs, which completely abolished insulin-stimulated glucose oxidation rates, an effect associated with decreased p-AKT and inactivation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme in glucose oxidation. Conclusion: This implicates the BCKAs, and not BCAAs, as the actual mediators of cardiac insulin resistance and suggests that lowering cardiac BCKAs can be used as a therapeutic strategy to improve insulin sensitivity in the heart.

AB - Backgrounds: Branched chain amino acid (BCAA) oxidation is impaired in cardiac insulin resistance, leading to the accumulation of BCAAs and the first products of BCAA oxidation, the branched chain ketoacids. However, it is not clear whether it is the BCAAs, BCKAs or both that are mediating cardiac insulin resistance. To determine this, we produced mice with a cardiac-specific deletion of BCAA aminotransferase (BCATm−/−), the first enzyme in the BCAA oxidation pathway that is responsible for converting BCAAs to BCKAs. Methods: Eight-week-old BCATm cardiac specific knockout (BCATm−/−) male mice and their α-MHC (myosin heavy chain) - Cre expressing wild type littermates (WT-Cre+/+) received tamoxifen (50 mg/kg i.p. 6 times over 8 days). At 16-weeks of age, cardiac energy metabolism was assessed in isolated working hearts. Results: BCATm−/− mice have decreased cardiac BCAA oxidation rates, increased cardiac BCAAs and a reduction in cardiac BCKAs. Hearts from BCATm−/− mice showed an increase in insulin stimulation of glucose oxidation and an increase in p-AKT. To determine the impact of reversing these events, we perfused isolated working mice hearts with high levels of BCKAs, which completely abolished insulin-stimulated glucose oxidation rates, an effect associated with decreased p-AKT and inactivation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme in glucose oxidation. Conclusion: This implicates the BCKAs, and not BCAAs, as the actual mediators of cardiac insulin resistance and suggests that lowering cardiac BCKAs can be used as a therapeutic strategy to improve insulin sensitivity in the heart.

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Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODS de las Naciones Unidas

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