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Background  Long chain acyl‐CoA synthetases ( ACSL ) catalyze long‐chain fatty acids ( FA ) conversion to acyl‐CoAs. Temporal  ACSL 1 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  Hif1 α‐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.

journal of the american heart association

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