Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin

Jonathan C Schisler; Trisha J Grevengoed; Florencia Pascual; Daniel E Cooper; Jessica M Ellis; David S Paul; Monte S Willis; Cam Patterson; Wei Jia; Rosalind A Coleman

doi:10.1161/jaha.114.001136

Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin

Jonathan C Schisler, Trisha J Grevengoed, Florencia Pascual, Daniel E Cooper, Jessica M Ellis, David S Paul, Monte S Willis, Cam Patterson, Wei Jia, Rosalind A Coleman

20 Citations (Scopus)

Abstract

Background: Long chain acyl-CoA synthetases (ACSL) catalyze long-chain fatty acids (FA) conversion to acyl-CoAs. Temporal ACSL1 inactivation in mouse hearts (Acsl1^H-/-) impaired FA oxidation and dramatically increased glucose uptake, glucose oxidation, and mTOR activation, resulting in cardiac hypertrophy. We used unbiased metabolomics and gene expression analyses to elucidate the cardiac cellular response to increased glucose use in a genetic model of inactivated FA oxidation. Methods and Results: Metabolomics analysis identified 60 metabolites altered in Acsl1^H-/- hearts, including 6 related to glucose metabolism and 11 to cysteine and glutathione pathways. Concurrently, global cardiac transcriptional analysis revealed differential expression of 568 genes in Acsl1^H-/- hearts, a subset of which we hypothesized were targets of mTOR; subsequently, we measured the transcriptional response of several genes after chronic mTOR inhibition via rapamycin treatment during the period in which cardiac hypertrophy develops. Hearts from Acsl1^H-/- mice increased expression of several Hif1a-responsive glycolytic genes regulated by mTOR; additionally, expression of Scl7a5, Gsta1/2, Gdf15, and amino acid-responsive genes, Fgf21, Asns, Trib3, Mthfd2, were strikingly increased by mTOR activation. Conclusions: The switch from FA to glucose use causes mTOR-dependent alterations in cardiac metabolism. We identified cardiac mTOR-regulated genes not previously identified in other cellular models, suggesting heart-specific mTOR signaling. Increased glucose use also changed glutathione-related pathways and compensation by mTOR. The hypertrophy, oxidative stress, and metabolic changes that occur within the heart when glucose supplants FA as a major energy source suggest that substrate switching to glucose is not entirely benign.

Original language	English
Article number	e001136
Journal	American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease
Volume	4
Issue number	2
Number of pages	16
ISSN	2047-9980
DOIs	https://doi.org/10.1161/jaha.114.001136
Publication status	Published - Feb 2015
Externally published	Yes

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JAHA.114.001136Final published version, 1.66 MBLicence: CC BY-NC-ND

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Schisler, J. C., Grevengoed, T. J., Pascual, F., Cooper, D. E., Ellis, J. M., Paul, D. S., Willis, M. S., Patterson, C., Jia, W., & Coleman, R. A. (2015). Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin. American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease, 4(2), Article e001136. https://doi.org/10.1161/jaha.114.001136

Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin. / Schisler, Jonathan C; Grevengoed, Trisha J; Pascual, Florencia et al.
In: American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease, Vol. 4, No. 2, e001136, 02.2015.

Research output: Contribution to journal › Journal article › Research › peer-review

Schisler, JC, Grevengoed, TJ, Pascual, F, Cooper, DE, Ellis, JM, Paul, DS, Willis, MS, Patterson, C, Jia, W & Coleman, RA 2015, 'Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin', American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease, vol. 4, no. 2, e001136. https://doi.org/10.1161/jaha.114.001136

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title = "Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin",

abstract = "Background: Long chain acyl-CoA synthetases (ACSL) catalyze long-chain fatty acids (FA) conversion to acyl-CoAs. Temporal ACSL1 inactivation in mouse hearts (Acsl1H-/-) impaired FA oxidation and dramatically increased glucose uptake, glucose oxidation, and mTOR activation, resulting in cardiac hypertrophy. We used unbiased metabolomics and gene expression analyses to elucidate the cardiac cellular response to increased glucose use in a genetic model of inactivated FA oxidation. Methods and Results: Metabolomics analysis identified 60 metabolites altered in Acsl1H-/- hearts, including 6 related to glucose metabolism and 11 to cysteine and glutathione pathways. Concurrently, global cardiac transcriptional analysis revealed differential expression of 568 genes in Acsl1H-/- hearts, a subset of which we hypothesized were targets of mTOR; subsequently, we measured the transcriptional response of several genes after chronic mTOR inhibition via rapamycin treatment during the period in which cardiac hypertrophy develops. Hearts from Acsl1H-/- mice increased expression of several Hif1a-responsive glycolytic genes regulated by mTOR; additionally, expression of Scl7a5, Gsta1/2, Gdf15, and amino acid-responsive genes, Fgf21, Asns, Trib3, Mthfd2, were strikingly increased by mTOR activation. Conclusions: The switch from FA to glucose use causes mTOR-dependent alterations in cardiac metabolism. We identified cardiac mTOR-regulated genes not previously identified in other cellular models, suggesting heart-specific mTOR signaling. Increased glucose use also changed glutathione-related pathways and compensation by mTOR. The hypertrophy, oxidative stress, and metabolic changes that occur within the heart when glucose supplants FA as a major energy source suggest that substrate switching to glucose is not entirely benign.",

author = "Schisler, {Jonathan C} and Grevengoed, {Trisha J} and Florencia Pascual and Cooper, {Daniel E} and Ellis, {Jessica M} and Paul, {David S} and Willis, {Monte S} and Cam Patterson and Wei Jia and Coleman, {Rosalind A}",

note = "{\textcopyright} 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.",

year = "2015",

month = feb,

doi = "10.1161/jaha.114.001136",

language = "English",

volume = "4",

journal = "American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease",

issn = "2047-9980",

publisher = "Wiley-Blackwell",

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TY - JOUR

T1 - Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin

AU - Schisler, Jonathan C

AU - Grevengoed, Trisha J

AU - Pascual, Florencia

AU - Cooper, Daniel E

AU - Ellis, Jessica M

AU - Paul, David S

AU - Willis, Monte S

AU - Patterson, Cam

AU - Jia, Wei

AU - Coleman, Rosalind A

PY - 2015/2

Y1 - 2015/2

N2 - Background: Long chain acyl-CoA synthetases (ACSL) catalyze long-chain fatty acids (FA) conversion to acyl-CoAs. Temporal ACSL1 inactivation in mouse hearts (Acsl1H-/-) impaired FA oxidation and dramatically increased glucose uptake, glucose oxidation, and mTOR activation, resulting in cardiac hypertrophy. We used unbiased metabolomics and gene expression analyses to elucidate the cardiac cellular response to increased glucose use in a genetic model of inactivated FA oxidation. Methods and Results: Metabolomics analysis identified 60 metabolites altered in Acsl1H-/- hearts, including 6 related to glucose metabolism and 11 to cysteine and glutathione pathways. Concurrently, global cardiac transcriptional analysis revealed differential expression of 568 genes in Acsl1H-/- hearts, a subset of which we hypothesized were targets of mTOR; subsequently, we measured the transcriptional response of several genes after chronic mTOR inhibition via rapamycin treatment during the period in which cardiac hypertrophy develops. Hearts from Acsl1H-/- mice increased expression of several Hif1a-responsive glycolytic genes regulated by mTOR; additionally, expression of Scl7a5, Gsta1/2, Gdf15, and amino acid-responsive genes, Fgf21, Asns, Trib3, Mthfd2, were strikingly increased by mTOR activation. Conclusions: The switch from FA to glucose use causes mTOR-dependent alterations in cardiac metabolism. We identified cardiac mTOR-regulated genes not previously identified in other cellular models, suggesting heart-specific mTOR signaling. Increased glucose use also changed glutathione-related pathways and compensation by mTOR. The hypertrophy, oxidative stress, and metabolic changes that occur within the heart when glucose supplants FA as a major energy source suggest that substrate switching to glucose is not entirely benign.

AB - Background: Long chain acyl-CoA synthetases (ACSL) catalyze long-chain fatty acids (FA) conversion to acyl-CoAs. Temporal ACSL1 inactivation in mouse hearts (Acsl1H-/-) impaired FA oxidation and dramatically increased glucose uptake, glucose oxidation, and mTOR activation, resulting in cardiac hypertrophy. We used unbiased metabolomics and gene expression analyses to elucidate the cardiac cellular response to increased glucose use in a genetic model of inactivated FA oxidation. Methods and Results: Metabolomics analysis identified 60 metabolites altered in Acsl1H-/- hearts, including 6 related to glucose metabolism and 11 to cysteine and glutathione pathways. Concurrently, global cardiac transcriptional analysis revealed differential expression of 568 genes in Acsl1H-/- hearts, a subset of which we hypothesized were targets of mTOR; subsequently, we measured the transcriptional response of several genes after chronic mTOR inhibition via rapamycin treatment during the period in which cardiac hypertrophy develops. Hearts from Acsl1H-/- mice increased expression of several Hif1a-responsive glycolytic genes regulated by mTOR; additionally, expression of Scl7a5, Gsta1/2, Gdf15, and amino acid-responsive genes, Fgf21, Asns, Trib3, Mthfd2, were strikingly increased by mTOR activation. Conclusions: The switch from FA to glucose use causes mTOR-dependent alterations in cardiac metabolism. We identified cardiac mTOR-regulated genes not previously identified in other cellular models, suggesting heart-specific mTOR signaling. Increased glucose use also changed glutathione-related pathways and compensation by mTOR. The hypertrophy, oxidative stress, and metabolic changes that occur within the heart when glucose supplants FA as a major energy source suggest that substrate switching to glucose is not entirely benign.

U2 - 10.1161/jaha.114.001136

DO - 10.1161/jaha.114.001136

M3 - Journal article

C2 - 25713290

SN - 2047-9980

VL - 4

JO - American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease

JF - American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease

IS - 2

M1 - e001136

ER -

Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin

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