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 Willis, Cam Patterson, Wei Jia, Rosalind A. Coleman

Research output: Contribution to journalArticle

14 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 languageEnglish (US)
Article numbere001136
JournalJournal of the American Heart Association
Volume4
Issue number2
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Sirolimus
Glutathione
Glucose
Fatty Acids
Genes
Metabolomics
Cardiomegaly
Coenzyme A Ligases
Gene Expression
Acyl Coenzyme A
Genetic Models
Hypertrophy
Cysteine
Oxidative Stress
Amino Acids

Keywords

  • acyl-CoA synthetase
  • Fuel switching
  • Glutathione
  • MTOR
  • Oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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; Cooper, Daniel E.; Ellis, Jessica M.; Paul, David S.; Willis, Monte; Patterson, Cam; Jia, Wei; Coleman, Rosalind A.

In: Journal of the American Heart Association, Vol. 4, No. 2, e001136, 01.01.2015.

Research output: Contribution to journalArticle

Schisler, Jonathan C. ; Grevengoed, Trisha J. ; Pascual, Florencia ; Cooper, Daniel E. ; Ellis, Jessica M. ; Paul, David S. ; Willis, Monte ; Patterson, Cam ; Jia, Wei ; Coleman, Rosalind A. / Cardiac energy dependence on glucose increases metabolites related to glutathione and activates metabolic genes controlled by mechanistic target of rapamycin. In: Journal of the American Heart Association. 2015 ; Vol. 4, No. 2.
@article{6a510187284c43488732c4de5b47a6dc,
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 (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.",
keywords = "acyl-CoA synthetase, Fuel switching, Glutathione, MTOR, Oxidative stress",
author = "Schisler, {Jonathan C.} and Grevengoed, {Trisha J.} and Florencia Pascual and Cooper, {Daniel E.} and Ellis, {Jessica M.} and Paul, {David S.} and Monte Willis and Cam Patterson and Wei Jia and Coleman, {Rosalind A.}",
year = "2015",
month = "1",
day = "1",
doi = "10.1161/JAHA.114.001136",
language = "English (US)",
volume = "4",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "2",

}

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

AU - Patterson, Cam

AU - Jia, Wei

AU - Coleman, Rosalind A.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

KW - acyl-CoA synthetase

KW - Fuel switching

KW - Glutathione

KW - MTOR

KW - Oxidative stress

UR - http://www.scopus.com/inward/record.url?scp=85003906012&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85003906012&partnerID=8YFLogxK

U2 - 10.1161/JAHA.114.001136

DO - 10.1161/JAHA.114.001136

M3 - Article

VL - 4

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 2

M1 - e001136

ER -