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Metabolic and transcriptional alterations observed in the early stages of cardiac substrate switching hint at novel mTOR‐regulated hypertrophy signaling pathways
Author(s) -
Pascual Florencia,
Schisler Jonathan C.,
Grevengoed Trisha J.,
Coleman Rosalind A.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.276.1
Subject(s) - medicine , endocrinology , pi3k/akt/mtor pathway , biology , p70 s6 kinase 1 , muscle hypertrophy , glycolysis , metabolism , signal transduction , biochemistry
Cardiomyocyte‐specific deficiency of long‐chain acyl‐CoA synthetase 1 ( Acsl1 H −/− ) results in a block in FA oxidation, rendering the heart dependent on the oxidation of glucose for contractile energy. Ten weeks after temporally‐induced Acsl1 inactivation, knockout hearts exhibit a 90% reduction in total ACSL activity and FA oxidation, and a compensatory increase in glucose uptake, as well as the development of mTOR‐mediated hypertrophy and diastolic dysfunction. Concomitant treatment with the mTOR inhibitor rapamycin for 10 weeks prevents cardiac hypertrophy due to the attenuation in the abnormal expression of hypertrophy‐associated genes as well as a block in ventricular S6K phosphorylation, suggesting heart‐specific mTOR signaling. The current work examines the early changes in gene expression, metabolites, and cardiac function as the Acsl1 ‐deficient heart adapts to the loss of FA substrate. Two weeks after cardiac‐specific Acsl1 ablation, ACSL activity decreased 60% and glucose and FA uptake were markedly altered, consistent with a shift toward glycolytic oxidation. Strikingly, this partial inhibition of FA activation was sufficient to elicit cardiac hypertrophy, the development of which was reversed by concomitant rapamycin treatment. No significant changes were observed in plasma glucose, NEFA, free glycerol or TAG, indicating that systemic metabolic homeostasis was not affected by short‐term cardiac Acsl1 deficiency. However, rapamycin‐responsive changes to the metabolic fingerprint and transcriptional response of Acsl1 H −/− hearts were observed, many of which were unique to the two week time point. Notably, alterations in the rapamycin‐sensitive mTOR genes identified in the ten week cardiac Acsl1 inactivation model were not evident at two weeks, despite the observed development of cardiac hypertrophy in both temporal knockout models. In addition, changes in expression of fibrosis genes were detected only in the short‐term Acsl1 abrogation model. Taken as a whole, these results support the notion that cardiac hypertrophy can develop via a novel pathway. Additional analyses of microarray and metabolomic data, as well as histological studies of fibrosis and hypertrophy, will allow us to elucidate the interrelationship between hypertrophy, cardiac dysfunction, and substrate use in heart. Support or Funding Information Supported by DK59935 and a grant from the American Heart Association 12GRNT12030144.